congenital and acquire immunodeficiency
DESCRIPTION
Congenital and acquire Immunodeficiency. Wei Chen, Associate professor Institute of Immunology E-mail:[email protected] http://mypage.zju.edu.cn/566 8888. Objectives. To understand the concept of immunodeficiency. - PowerPoint PPT PresentationTRANSCRIPT
Congenital and acquire
Immunodeficiency
Wei Chen Associate professorInstitute of Immunology
E-mailchenwei566zjueducnhttpmypagezjueducn566 8888
Objectives
1048698 To understand the concept of immunodeficiency
To know the main types of primary immunodeficiency diseases
1048698 Be able to describe characteristics and consequence of HIV infection
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Immunodeficiency
Defects in the development and functions of the immune system
Result in increased susceptibility to infections and in an increased incidence of certain cancers
Disorders caused by defective immunity are called immunodeficiency diseases
General feature of immunodeficiency diseases
The principal consequence of immunodeficiency is an increased susceptibility to infection
Patients with immunodeficiencies are also susceptible to certain types of cancer
Paradoxically certain immunodeficiencies are associated with an increased incidence of autoimmunity
Immunodeficiency may result from defects in lymphocyte development or activation or from defects in the effector mechanisms of innate and adaptive immunity
Classification Primary or congenital immunodeficiencies
Present at birthResult from genetic abnormalities in one or more components of the immune system
Secondary or acquired immunodeficienciesLater in lifeResult from infections malnutrition or treatments that cause loss or inadequate function of various components of the immune systemMost common is acquired immunodeficiency syndrome or AIDS
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Primary immunodeficiency diseases
Severe Combined Immunodeficiencies (SCID)
Antibody Deficiencies Defects in B Cell
Development and Activation
Defects in T Lymphocyte Activation and
Function
Defects in Innate Immunity
Multisystem Disorders with immunodeficiency
Features of immunodeficiency diseases
congenital immunodeficiencies caused by defects in lymphocyte maturation
Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies
characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help
Children with SCID usually have infections during the first year of life
Severe Combined Immunodeficiency Syndromes
(SCID)
Severe Combined Immunodeficiency Syndromes
(SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency ( 腺苷脱氨酶 )
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Objectives
1048698 To understand the concept of immunodeficiency
To know the main types of primary immunodeficiency diseases
1048698 Be able to describe characteristics and consequence of HIV infection
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Immunodeficiency
Defects in the development and functions of the immune system
Result in increased susceptibility to infections and in an increased incidence of certain cancers
Disorders caused by defective immunity are called immunodeficiency diseases
General feature of immunodeficiency diseases
The principal consequence of immunodeficiency is an increased susceptibility to infection
Patients with immunodeficiencies are also susceptible to certain types of cancer
Paradoxically certain immunodeficiencies are associated with an increased incidence of autoimmunity
Immunodeficiency may result from defects in lymphocyte development or activation or from defects in the effector mechanisms of innate and adaptive immunity
Classification Primary or congenital immunodeficiencies
Present at birthResult from genetic abnormalities in one or more components of the immune system
Secondary or acquired immunodeficienciesLater in lifeResult from infections malnutrition or treatments that cause loss or inadequate function of various components of the immune systemMost common is acquired immunodeficiency syndrome or AIDS
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Primary immunodeficiency diseases
Severe Combined Immunodeficiencies (SCID)
Antibody Deficiencies Defects in B Cell
Development and Activation
Defects in T Lymphocyte Activation and
Function
Defects in Innate Immunity
Multisystem Disorders with immunodeficiency
Features of immunodeficiency diseases
congenital immunodeficiencies caused by defects in lymphocyte maturation
Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies
characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help
Children with SCID usually have infections during the first year of life
Severe Combined Immunodeficiency Syndromes
(SCID)
Severe Combined Immunodeficiency Syndromes
(SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency ( 腺苷脱氨酶 )
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Immunodeficiency
Defects in the development and functions of the immune system
Result in increased susceptibility to infections and in an increased incidence of certain cancers
Disorders caused by defective immunity are called immunodeficiency diseases
General feature of immunodeficiency diseases
The principal consequence of immunodeficiency is an increased susceptibility to infection
Patients with immunodeficiencies are also susceptible to certain types of cancer
Paradoxically certain immunodeficiencies are associated with an increased incidence of autoimmunity
Immunodeficiency may result from defects in lymphocyte development or activation or from defects in the effector mechanisms of innate and adaptive immunity
Classification Primary or congenital immunodeficiencies
Present at birthResult from genetic abnormalities in one or more components of the immune system
Secondary or acquired immunodeficienciesLater in lifeResult from infections malnutrition or treatments that cause loss or inadequate function of various components of the immune systemMost common is acquired immunodeficiency syndrome or AIDS
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Primary immunodeficiency diseases
Severe Combined Immunodeficiencies (SCID)
Antibody Deficiencies Defects in B Cell
Development and Activation
Defects in T Lymphocyte Activation and
Function
Defects in Innate Immunity
Multisystem Disorders with immunodeficiency
Features of immunodeficiency diseases
congenital immunodeficiencies caused by defects in lymphocyte maturation
Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies
characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help
Children with SCID usually have infections during the first year of life
Severe Combined Immunodeficiency Syndromes
(SCID)
Severe Combined Immunodeficiency Syndromes
(SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency ( 腺苷脱氨酶 )
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Immunodeficiency
Defects in the development and functions of the immune system
Result in increased susceptibility to infections and in an increased incidence of certain cancers
Disorders caused by defective immunity are called immunodeficiency diseases
General feature of immunodeficiency diseases
The principal consequence of immunodeficiency is an increased susceptibility to infection
Patients with immunodeficiencies are also susceptible to certain types of cancer
Paradoxically certain immunodeficiencies are associated with an increased incidence of autoimmunity
Immunodeficiency may result from defects in lymphocyte development or activation or from defects in the effector mechanisms of innate and adaptive immunity
Classification Primary or congenital immunodeficiencies
Present at birthResult from genetic abnormalities in one or more components of the immune system
Secondary or acquired immunodeficienciesLater in lifeResult from infections malnutrition or treatments that cause loss or inadequate function of various components of the immune systemMost common is acquired immunodeficiency syndrome or AIDS
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Primary immunodeficiency diseases
Severe Combined Immunodeficiencies (SCID)
Antibody Deficiencies Defects in B Cell
Development and Activation
Defects in T Lymphocyte Activation and
Function
Defects in Innate Immunity
Multisystem Disorders with immunodeficiency
Features of immunodeficiency diseases
congenital immunodeficiencies caused by defects in lymphocyte maturation
Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies
characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help
Children with SCID usually have infections during the first year of life
Severe Combined Immunodeficiency Syndromes
(SCID)
Severe Combined Immunodeficiency Syndromes
(SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency ( 腺苷脱氨酶 )
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
General feature of immunodeficiency diseases
The principal consequence of immunodeficiency is an increased susceptibility to infection
Patients with immunodeficiencies are also susceptible to certain types of cancer
Paradoxically certain immunodeficiencies are associated with an increased incidence of autoimmunity
Immunodeficiency may result from defects in lymphocyte development or activation or from defects in the effector mechanisms of innate and adaptive immunity
Classification Primary or congenital immunodeficiencies
Present at birthResult from genetic abnormalities in one or more components of the immune system
Secondary or acquired immunodeficienciesLater in lifeResult from infections malnutrition or treatments that cause loss or inadequate function of various components of the immune systemMost common is acquired immunodeficiency syndrome or AIDS
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Primary immunodeficiency diseases
Severe Combined Immunodeficiencies (SCID)
Antibody Deficiencies Defects in B Cell
Development and Activation
Defects in T Lymphocyte Activation and
Function
Defects in Innate Immunity
Multisystem Disorders with immunodeficiency
Features of immunodeficiency diseases
congenital immunodeficiencies caused by defects in lymphocyte maturation
Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies
characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help
Children with SCID usually have infections during the first year of life
Severe Combined Immunodeficiency Syndromes
(SCID)
Severe Combined Immunodeficiency Syndromes
(SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency ( 腺苷脱氨酶 )
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Classification Primary or congenital immunodeficiencies
Present at birthResult from genetic abnormalities in one or more components of the immune system
Secondary or acquired immunodeficienciesLater in lifeResult from infections malnutrition or treatments that cause loss or inadequate function of various components of the immune systemMost common is acquired immunodeficiency syndrome or AIDS
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Primary immunodeficiency diseases
Severe Combined Immunodeficiencies (SCID)
Antibody Deficiencies Defects in B Cell
Development and Activation
Defects in T Lymphocyte Activation and
Function
Defects in Innate Immunity
Multisystem Disorders with immunodeficiency
Features of immunodeficiency diseases
congenital immunodeficiencies caused by defects in lymphocyte maturation
Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies
characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help
Children with SCID usually have infections during the first year of life
Severe Combined Immunodeficiency Syndromes
(SCID)
Severe Combined Immunodeficiency Syndromes
(SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency ( 腺苷脱氨酶 )
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Primary immunodeficiency diseases
Severe Combined Immunodeficiencies (SCID)
Antibody Deficiencies Defects in B Cell
Development and Activation
Defects in T Lymphocyte Activation and
Function
Defects in Innate Immunity
Multisystem Disorders with immunodeficiency
Features of immunodeficiency diseases
congenital immunodeficiencies caused by defects in lymphocyte maturation
Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies
characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help
Children with SCID usually have infections during the first year of life
Severe Combined Immunodeficiency Syndromes
(SCID)
Severe Combined Immunodeficiency Syndromes
(SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency ( 腺苷脱氨酶 )
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Primary immunodeficiency diseases
Severe Combined Immunodeficiencies (SCID)
Antibody Deficiencies Defects in B Cell
Development and Activation
Defects in T Lymphocyte Activation and
Function
Defects in Innate Immunity
Multisystem Disorders with immunodeficiency
Features of immunodeficiency diseases
congenital immunodeficiencies caused by defects in lymphocyte maturation
Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies
characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help
Children with SCID usually have infections during the first year of life
Severe Combined Immunodeficiency Syndromes
(SCID)
Severe Combined Immunodeficiency Syndromes
(SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency ( 腺苷脱氨酶 )
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Features of immunodeficiency diseases
congenital immunodeficiencies caused by defects in lymphocyte maturation
Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies
characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help
Children with SCID usually have infections during the first year of life
Severe Combined Immunodeficiency Syndromes
(SCID)
Severe Combined Immunodeficiency Syndromes
(SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency ( 腺苷脱氨酶 )
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
congenital immunodeficiencies caused by defects in lymphocyte maturation
Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies
characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help
Children with SCID usually have infections during the first year of life
Severe Combined Immunodeficiency Syndromes
(SCID)
Severe Combined Immunodeficiency Syndromes
(SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency ( 腺苷脱氨酶 )
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Congenital immunodeficiencies that affect both humoral and cell-mediated immunity are called combined immunodeficiencies
characterized by deficiencies of both B and T cells or only of T cells in the latter cases the defect in humoral immunity is due to the absence of T cell help
Children with SCID usually have infections during the first year of life
Severe Combined Immunodeficiency Syndromes
(SCID)
Severe Combined Immunodeficiency Syndromes
(SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency ( 腺苷脱氨酶 )
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Severe Combined Immunodeficiency Syndromes
(SCID)
Athymic - DiGeorge Syndrome
X-linked SCID (c deficiency)
Adenosine deaminase deficiency ( 腺苷脱氨酶 )
Jak3 kinase deficiency
Purine nucleoside phosphorylase deficiency
Bare lymphocyte syndrome
RAG1 and RAG2 deficiency
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Precursor T cell differentiation defect
Athymic - DiGeorge SyndromeSporadic microdeletion of 22q TBX1 gene (T-box1)Lack of T helper (Th) cells Cytotoxic T cells (CTL) and T regulatory (Treg) cellsB cells are present but T-dependent B cell responses are defectiveAnti-viral and anti-fungal immunity impairedDevelopmental defect in the 3rd and 4th pharyngeal pouch Results in facial defect and congenital heart disease
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
DiGeorge syndrome
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
X-Linked SCID Common Cytokine Receptor Gamma Chain (c) Deficiency
Most common form of SCID (40)
Responsible gene γcndash the common subunit of receptors for IL-2 IL-4 IL-7 IL-9 and IL-15
Very low T cells and NK cells with low to normal numbers of B cells
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Nude Athymic mouse
FOXN1 gene knock-out (autosomal recessive)HairlessShould be maintained in pathogen-free environmentT helper cell defectResults in impaired cytotoxic T cell activity and Th-dependent B cell responses due to Th cell defectAccept xenografts
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Antibody Deficiencies Defects in B Cell Development and
Activation
Brutonrsquos (X-linked) Agammaglobulinemia
Common Variable Immunodeficiency (CVID)
Autosomal Recessive Hyper-IgM Syndrome
B Cell Receptor Deficiencies
Selective IgA Deficiency
IgG Subclass Deficiency
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
XLA - BTK defect
Defect in B cell maturationGenetic disorder - gene on X-chromosomecodes for Brutonrsquos tyrosine kinase - BTK essential for B cell development
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Essential role of BTK
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Brutonrsquos X-linked Agammaglobulinemia
The absence of B cells in blood and IgG
x-linked recessive inheritance males
Child clinically well for first 6 months of life
Recurrent upperlower respiratory tract infections with encapsulated bacteria
Sepsis (败血症 ) meningitis (脑膜炎 ) skin infections
Paucity of lymphoid tissue (tonsils adenoids)
Treatment inject pooled gamma globulin preparations
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Common Variable Immunodeficiency
Panhypogammaglobulinemia (全丙种球蛋白过少血症 ) usually with lymphadenopathy and splenomegaly
Absence of clear abnormalities in T and B cell subsets
Chronicrecurrent respiratory infections diarrhea(腹泻 )
Tendency to develop autoimmunity and lymphoid malignancies
Linkage to HLA Class III Region in 23 of patients
One gene identified ICOS (B7h) (activation antigen on T cells)
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Defects in Innate Immunity
Phagocyte Deficiencies
Chronic granulomatous disease (CGD)
Leukocyte adhesion deficiency (LAD I)
Complement Deficiency
Defects in NK cells and other leukocytes the Cheacutediak-Higashi syndrome
Inherited defects in TLR Pathways NF-κB signaling and type I Interferons
IL-12IFN pathway deficiencies
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Congenital immunodeficiencies caused by defects in innate immunity
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Chronic Granulomatous Disease
Inability of phagocytes to generate hydrogen peroxide due to mutations in one of four proteins comprising the NADPH oxidase
Severe tissue infections with catalase positive organisms esp Staph aureus Serratia marcescens mycobacteria and fungi such as Aspergillus
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Chronic granulomatous disease
Note cervical nodal abscess(头颈淋巴结脓肿 )
Gingivitis and periodontitis (牙龈炎和牙周炎 )
Abscess indenting the oesophagus(食道脓肿 )
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
CGD patient with
skin infections
due to Serratia
marcescens
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Content
Introduction
Primary immunodeficiency diseases
Secondary immunodeficiency
diseases
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Secondary or acquired immunodeficiency diseases
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Human Immunodeficiency Virus
Discovered in 1983 by Luc Montagnier and Robert Gallo
Retrovirus (RNA virus)
HIV-1 (common) and HIV-2 (Africa)
Patients with low CD4+ T cells
Virus prevalent in homosexual promiscuous heterosexual iv drug users transfusion infants born to infected mothers
Opportunistic infections with Pnuemocystis carinii ( 卡氏肺囊虫 ) Candida albicans Mycobacterium avium etc
Patients with HIV have high incidence of cancers such as Kaposi sarcoma
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Kaposi Sarcoma
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Incidence of HIV
CDC 2008
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
HIV - The Virus
A retrovirus
Genetic material is RNA
Transcribed into DNA by RT (reverse transcriptase)
Copy (provirus) inserted into the host genome
When it is expressed to form new virions the cell lyses
Alternately it may remain latent in the cell for an extended period of time
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
The structure of human HIV-1
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Genes of human HIV-1
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
The life cycle of HIV-1
Infection of cells gp120 binds to CD4 and CXCR4 on T cells or CCR5 on DC and M
Production of viral DNA and its integration into the host genome
Expression of viral genes production of viral RNAs and then proteins to form a core structure
Production of viral particles the core structure migrates to the cell membrane acquires a lipid envelope from the host and the viral particle is shed
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
The life cycle of HIV-1
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Pathogenesis of AIDS
HIV establishes a latent infection in immune cells and may be reactivated to produce infectious virus This viral production leads to death of infected cells and uninfected lymphocytes subsequent immunodeficiencies and clinical AIDS
The depletion of CD4+ T cells after HIV infection is due to a cytopathic effect of the virus resulting from production of viral particles as well as death of uninfected cells
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Course of AIDS
ACUTE CHRONIC AIDS PHASE PHASE AIDS (lt200cellsmm3)
Anti-HIV AbCTL
Dissemination of virus Seeding of lymphoid organs
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
The pathogenesis of AIDS
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
The earliest innate and adaptive immune responses detected after HIV
transmission
Nat Rev Immunol 20101011
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Animal Models
Primate ModelHIV grows in chimpanzees but do not develop AIDSSimian immunodeficiency virus (SIVagm in African green monkey ndash no disease SIVmac in Macaques ndash AIDS like)
Mouse ModelGrows in Severe Combined Immunodeficiency (SCID) mice reconstituted with human lymphocytes
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
US Death Rates
25-44 years old
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Therapy and vaccination strategies
Several places in virus life-cycle that can be blocked
Attachmententry
Reverse transcription
Integration
Proteolysis
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Reverse Transcription
AZT (zidovudine)Nucleoside analog - is incorporated into growing chain and causes terminationSide effectsResistant mutants develop
NevirapineInhibits action of RT
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Protease Inhibitors
Blocks action of protease
Huge breakthrough
Responsible for rapid drop in number of deaths in US
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Combination Therapy
HAART is a combination therapy
Highly Active Anti-Retroviral Therapy
Two nucleoside analogs and one protease inhibitor
Helps to prevent rapid mutating viruses from developing resistance
Can reduce virus to undetectable levels
Expensive ($15000yr)
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Therapies
Ongoing work to develop drugs to interfere with integration and with attachmententry
Takes many years to pass tests for safety and efficacy
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect
Vaccines
Has been much harder to develop a vaccine for HIV than it has been for other viruses
Results have been disappointing
Can get antibodies but they donrsquot protect