hiv pathogenesis and natural course of the disease unit 4 hiv care and art: a course for physicians

HIV Pathogenesis and Natural Course of the Disease

Unit 4HIV Care and ART: A Course for Physicians

Pathogenesis and Natural Course of the Disease 2

Learning Objectives

■ Discuss HIV molecular biology and virology

■ Describe immunological response against infections

■ Explain the effect of HIV on the immune system and how HIV establishes a chronic infection

■ Identify characteristics that make HIV disease chronic and incurable

■ Understand the natural course of the disease


Virology of HIV


Characteristics of HIV

■ Classification

■ Family of retroviruses (RNA -> DNA -> RNA)

■ Subfamily of lente (slow) viruses

■ Cytopathic to cells that replicate it

■ Infects many cells types and is latent in some cells

■ Infects and depletes CD4 lymphocytes

■ Causes cell-mediated immunosuppression


HIV Strains

■ HIV-1 Group M (main), the cause of the AIDS epidemic

■ HIV-2, a less virulent retrovirus causing an epidemic in West Africa


HIV-1 and HIV-2 Differ in Multiple Ways■ Accessory genes

■ HIV-1 vpu

■ HIV-2 vpx

■ Distribution

■ HIV-1 – global pandemic

■ HIV-2 – West Africa

■ Rate of progression of severe immunosuppression

■ HIV-1 – median time to AIDS = 10 years

■ HIV-2 – median time to AIDS = longer, but ?


Classification of HIV-1

■ Groups

■ M (major) with 9 subtypes (clades)

■ O (outlier)

■ N (reported only in Cameroon)

■ Group M’s clades (related viruses)

■ Named with letters A to K, with many recombinants between parts of HIV from two clades

■ Differ in geographic distribution

■ Differ from each other by about 30% in the env coding sequences and 14% of the gag code sequences


HIV Clades

■ HIV rapidly evolves by two mechanisms:

■ Mutation - changes in single nucleosides of the RNA

■ Recombination – combinations of long RNA sequences from two distinct HIV strains

■ Distinct genetic subgroups, or clades, of the M group of HIV have evolved and become dominate in specific geographic regions

■ A in Central Africa

■ B in North American and Europe

■ C in Southern and Eastern Africa

■ Several clades (e.g., A/G ad A/E) are recombinants


Geographic Distribution


Structure of HIV



■ HIV infect cells that express CD4 receptor molecules

■ CD-4 receptor molecules are expressed by T-helper cells and monocyte-macrophage cell lines

■ Successful entry of the virus to a target cell also requires cellular co-receptors


Characteristics of HIV (2)

■ A fusion co-receptor is designated CXCR5 for T-cell tropic stain and CCR4 for monocyte-macrophage tropic strains

■ The receptor and co-receptors of CD4 cells interact with HIV’s gp-120 and gp-41 proteins during entry into a cell


HIV ReceptorsHIV Receptors

Levy JA, NEJM, 335(20); 1528-1530

HIV and Cellular Receptors

Role of Chemokine Receptors in HIV EntryHost Cell Membrane Fusion Via CXCR4


Cell cytoplasm

Cell nucleus


Life Cycle of HIV: Replication

■ Reverse transcription converse HIV RNA into proviral DNA

■ Importation to cell nucleus

■ Integration of proviral to host-cell DNA

■ Cellular activation causes transcription (copying) of HIV DNA back to RNA

■ Some RNA translated to HIV proteins

■ Other RNA moved to cell membrane

■ HIV assembled under cell membrane and budded from cell

■ Proteases convert immature to infectious HIV


HIV life cycle

Fusion-Inhibitors

Summary of Life Cycle of HIV and Sites of Drug Action



Once infection is established, the virus homes itselfmainly in the lymphoid and, to a lesser extent, in thecirculation.


Cell free HIV CD40—CD40

Skin or mucosa

24 hours 48 hours

1. HIV co receptors, CD4 + chemokine receptor CC5

Immature Dendritic cell

3. Mature Dendritic cell in regional LN undergoes a single replication, which transfers HIV to T-cell

Via lymphatics or circulation

T-cell

PEP

Burst of HIV replication

2. Selective of macrophage-tropic HIV

Early Phases of HIV Entry and Replication at Mucosal Surfaces

Spread of HIV in Host Tissues


Enhanced: Dendritic Cell’s HIV Infectivity to CD4 T-cell

CD4


Immunology and HIV Infection


Types of Normal Immune Responses

■ Innate – non-specific, “natural,” no prior contact required

■ Mediated through neutrophils, macrophages, circulating binding proteins, and natural killer lymphocytes

■ Acquired – specific, learned from contact with pathogens

■ Mediated through T (cellular signalizing) and B (antibody producing) lymphocytes and macrophages


The Normal Immune Response

■ Normal host defense in response to a foreign antigen culminates in a rapid and efficient elimination of a non-self substance

■ The process of elimination of a foreign antigen involves effector-cell activity and their interaction through soluble cellular secretions (cytokines)


Specific Normal Immune Response


Normal Immune-Cell Interaction

CTL

CTL

plasma

CD-4-4


Specific Immune Response


Peculiar Characteristics of HIV

HIV is a unique infection in that:

■ The virus is not cleared, except partially in the early period of infection

■ A chronic infection is established, and it persists with varying degrees of viral replication. The viral replication continues for about eight to ten years before bringing in significant immuno-suppresion

■ There is no virological latency

Infected CD4 T-lymphocyte

Modified; South Carolina Medical Library

HIV


Viral Dynamics of HIV Infection

■ Viral replication is continuous in all stages (early, during clinical latency and in advanced stages)

■ Half life of a virion is about 6 hours, while an infected cell has a life span of 1.6 days

■ Daily about 1010 virions are produced and cleared from the circulation

■ Average generation time of HIV is 2.6 days


Viral Set Point

■ The level of steady-state viremia (set-point) at six months to one year after infection has and important prognostic implication for progression of HIV disease

■ Those with a high viral set-point have faster progression to AIDS, if not treated


Reasons for Persistent Viremia

Despite robust immune reaction, HIV evadeselimination by the immune system due to:

■ High level of viral mutation

■ Large pool of latently infected cells that cannot be eliminated by viral-specific CTLs

■ Virus homes in lymphoid organs, while antibody is in the circulation

■ Exhaustion of CD8 T-lymphocytes by excessive antigen stimulation


Reasons for Persistent Viremia (2)

■ Down regulation of HLA-1 molecule in HIV infected cells

■ HIV attacks CD-4 T-cells, which are central to both humoral and-cell mediated immunity

■ HIV seeds itself in areas of the body where sufficient antibodies might not reach, e.g., the central nervous system


Pathogenesis of HIV

■ HIV infection is a disease characterized by a profound immunodeficiency from progressive decline of T-helper cells

■ The pathogenetic mechanism of HIV disease is multifactorial and multiphasic and it differs in different stage of the disease


Effects of Cellular Activation

■ Quiescent but infected CD4 T-cells start to transcript, making viral spread more efficient

■ Cellular activation induces expression of receptors for HIV

■ Chronic stimulation favors programmed cell death (apoptosis) to CD4, CD8 and B-cells

■ Significant increase in the release of cytokines


Effects of Cellular Activation (2)

■ Brings about up-regulation of viral expression and cellular activation

■ Initiates auto-immune phenomena

■ Brings about compromised immune response to broad spectrum of antigens

■ Co-infection (TB, CMV, etc.) also induces viral replication


Cytokines in HIV

■ The immune system is regulated by a complex of immuno-regulatory cytokines

■ Cytokines are cellular products that induce or suppress cellular activity

■ Inducers of HIV expression include: IL-1, IL-2, IL-3, IL-6, IL-12, TNF-Alfa, TNL-beta, M-CSF and GM-CSF

■ The most potent inducers are pro-inflammatory cytokines, TNF-Alfa, IL-1and IL-6, which are products of macrophages


Cytokines in HIV (2)

■ T-helper cells are classified as TH-1 and TH-2 based on the type cytokines they release

■ TH-1 type secrete IL-2 and INF-Alfa, which favor cell-mediated immune response

■ TH-2 type secrete IL-4, IL-5 and IL-10, which favor humoral immune response

■ HIV-infected individuals show decreased TH-1 type response in relation to TH-2


Effect of IL-2


T-cell Abnormalities

■ Late in the course of illness, there are qualitative and quantitative abnormalities

■ T-cell abnormalities detected in the course of the illness are manifested as CD4 and CD8 abnormalities


CD4 Cell Abnormalities

■ Defective T-cell cloning and colony-forming efficiency

■ Impaired expression of IL-2

■ Defective IL-2 and INF-Alfa production

■ Decreased help to B-cells in production of immunogloblins

■ Marked reduction in their number


CD8 Cell Abnormalities

■ Remain high after primary infection and throughout the latent period

■ In advanced stage, there is marked reduction

■ HIV-specific clones of CD8 CTLs that are present in the early phase of illness disappear in advanced period

■ In the face of depleting CD4, the homeostatic mechanism responsible for maintaining total T-cells in a normal range replaces CD8, leading to CD8 lymphocytosis


Mechanism of CD4 Cell Depletion

■ HIV-mediated direct cytopathicity (singe cell killing)

■ HIV-mediated syncytia formation

■ Defect in CD4 T-cell regeneration in relation to the rate of destruction

■ Maintenance of homeostasis of total T-lymphocytes (decreased CD4, increased CD8)


Mechanism of CD4 Cell Depletion (2)

■ HIV-specific immune response (killing of virally infected and innocent cells)

■ Auto-immune mechanism

■ Programmed cell death (apoptosis)

Apoptosis (Programmed Cell Death)

Guisoppe et.al. NEJM 328,1993


B-cell Activity in HIV

■ There is no quantitative abnormality

■ Has abnormal activation with spontaneous proliferation and IG, IL-6 and TNF-Alfa secretion

■ B-cells are defective for antigen stimulation

■ HIV can directly stimulate B-cells leading to hypergammaglobulinemia

■ Cannot mount sufficient humoral immunity to common bacterial antigen


Monocyte Macrophage Activity

■ Circulating monocytes are generally normal in HIV infection

■ Cytopathic effect of HIV to monocyte macrophage is low

■ HIV can intensely replicate in monocyte macrophage cell line

■ There is defective function, like in antigen presentation, chemotaxis, secretion of IL-1 and in induction of T-cell response


Humoral Immune Response

■ Neutralizing antibodies appear following primary viremia with CTLs

■ Antibodies are produced to multiple epitopes of HIV

■ HIV antibodies are used as diagnostic tool

■ Generally their preventive role is unknown


Primary HIV Infection

■ Following primary infection there is initial viremia

■ The phenomena of dissemination of virus to lymphoid organs is the major factor in establishment of chronic and persistent infection

■ Whatever the route of entry the virus, it reaches a lymphoid organ, where it bases itself and replicates extensively

■ Intense replication brings about a burst of viremia which triggers HIV-specific antibody


Primary HIV Infection (2)

■ Primary viremia lasts several weeks

■ The set-point (steady state) plasma viremia at six months to one year correlates with disease progression (those with low set point develop advanced disease slowly)


Pathogenesis of HIV Infection: No Progression with Low-level Viremia

CD4

RNA

Primary HIV Chronic Non-progressive HIV Infection

RNA Set Point ~ 103


Pathogenesis: Average Progression with Median-Level Viremia

RNA

CD4

5

Primary HIV Slowly Progressive HIV AIDS

Years

1 10

RNA Set Point ~104


Pathogenesis: Rapid Progression with High-Level Viremia

RNA

CD4

32

Primary HIV AIDS

Years

RNA Set Point ~ 106


HIV RNA Levels Predict Progression to AIDS


Relating Disease Progression to Plasma HIV-1 RNA Level and CD4 Cell Count

Adapted with permission from Coffin. AIDS. 1996;10(suppl 3):S75-S84.

Viral Load

1,000

10,000

100,000

100

CD4 COUNT1000 900 800 700 600 500

400

300

200

+


Chronic and Persistent Infection

■ HIV-specific antibody partially clears the virus

■ There is clinical latency

■ Initial clones of CD8 lymphocytes CTLs, which partially control viremia, are later lost

■ There is progressive drop in CD4 T-cells


Advanced HIV Disease

■ CD4 cells fall below critical level: <200cells/ml

■ Patients present with OIs or malignancy

■ Higher degree of viremia due to destruction of lymphoid organs

Natural History of HIV Disease from HIV Transmission to Death (no ARV)

• Fauci AS, Pantaleo G, Stanley, Weissman D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med 1996;124:654-63.


Window Period: Untreated Clinical Course

--------------------------------------------PCRP24ELISA

0 2 3 4Weeks since infection

a b Time from a to b is the window period

viremia

antibodyAsymptomatic

Acute HIV syndromePrimary HIV infection

Source: S Conway and J.G Bartlett, 2003

years


Laboratory Markers of HIV Infection – Immune Suppression

Markers of immunologic damage by HIV: subsets of T-lymphocytes

■ Functional surface proteins (CD4 and CD8) used to count

■ Normal Values

■ Helper / CD4 + cell count = 400-1200

■ Suppressor/ CD8 + cell count = 400-800


Key Points

■ HIV infection is a chronic disease

■ The immune system is the target of HIV

■ Clinically there are different stages based on immunocompetence

■ During clinical latency, there is no virological latency


Key Points (2)

■ The effect of immune system delays the onset of clinical disease

■ HIV can be suppressed, but there is no cure

■ Ultimately the immune system is destroyed, with a few exceptions

hiv pathogenesis and natural course of the disease unit 4 hiv care and art: a course for physicians

Documents

hiv pathogenesis

disease8 hiv clades

group of hiv

disease5 hiv strains

vpu hiv

effect of hiv

years hiv

hiv care