Human Herpesviruses

Human herpesviruses• Three subfamilies (genome structure, tissue tropism,

cytopathologic effect, site of latent infection)• Alphaherpesvirinae:Human herpesvirus 1 Herpes simplex type 1 HSV-1Human herpesvirus 2 Herpes simplex type 2 HSV-2Human herpesvirus 3 Varicella-zoster virus VZV• GammaherpesvirinaeHuman herpesvirus 4 Epstein-Barr virus EBVHuman herpesvirus 8 Kaposi’s sarcoma related virus HHV-8• Betaherpesvirinae Human herpesvirus 5 Cytomegalovirus CMVHuman herpesvirus 6Herpes lymphotropic virus HHV-6Human herpesvirus 7 Human herpesvirus 7 HHV-7

Herpesviruses• Unique Features of Herpesviruses• Herpesviruses have large, enveloped icosadeltahedral capsids containing

double-stranded DNA genomes. • Herpesviruses encode many proteins that manipulate the host cell and

immune response. • Herpesviruses encode enzymes (DNA polymerase) that promote viral DNA

replication and that are good targets for antiviral drugs. • DNA replication and capsid assembly occurs in the nucleus. • Virus is released by exocytosis, cell lysis, and through cell-cell bridges. • Herpesviruses can cause lytic, persistent, latent, and, for Epstein-Barr

virus, immortalizing infections. • Herpesviruses are ubiquitous. • Cell-mediated immunity is required for control.

Human herpesviruses

They have common:• Virion morphology• Basic mode of replication• Capacity to establish latent and recurrent infections, in case

of EBV immortalizing infections• Ubiquitous• Usually cause benign disease especially in children• In immunosuppressed people they cause significant morbidity

and mortality

Table 54-1. Properties Distinguishing the Herpesviruses

Subfamily Virus Primary Target Cell Site of Latency Means of Spread

Alphaherpesvirinae

Human herpesvirus 1 Herpes simplex type 1 Mucoepithelial cells Neuron Close contact

Human herpesvirus 2 Herpes simplex type 2 Mucoepithelial cells Neuron Close contact (sexually transmitted disease)

Human herpesvirus 3 Varicella-zoster virus Mucoepithelial cells Neuron Respiratory and close contact

Gammaherpesvirinae

Human herpesvirus 4 Epstein-Barr virus B cells and epithelial cells B cell Saliva (kissing disease)

Human herpesvirus 8 Kaposi's sarcoma-related virus

Lymphocyte and other cells B cell Close contact (sexual), saliva?

Betaherpesvirinae

Human herpesvirus 5 Cytomegalovirus Monocyte, lymphocyte, and epithelial cells

Monocyte, lymphocyte, and ?

Close contact, transfusions, tissue transplant, and congenital

Human herpesvirus 6 Herpes lymphotropic virus T cells and ? T cells and ? Respiratory and close contact?

Human herpesvirus 7 Human herpesvirus 7 T cells and ? T cells and ? ?

           

                                                                                             

               

icosadeltahedral capsid and an envelope

Human herpesviruses-DNA polymerase:-viral DNA replication

-good target for antiviral drugs.

-DNA replication and assembly:nucleus-buds from nuclear membrane, released by

exocytosis and cell lysis.-lytic,persistant, latent, for EBV immortalizing

infections

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Disease Mechanisms for Herpes Simplex Viruses

Disease is initiated by direct contact and depends on infected tissue (e.g., oral, genital, brain). Virus causes direct cytopathologic effects. Virus avoids antibody by cell-to-cell spread (syncytia). Virus establishes latency in neurons (hides from immune response). Virus is reactivated from latency by stress or immune suppression. Cell-mediated immunity is required for resolution with limited role for antibody. Cell-mediated immunopathologic effects contribute to symptoms.

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Herpes simplex virus

• Two types: HSV-1 and HSV-2• HSV can infect most types of human cells and

even cells of other species. • Lytic infection of fibroblasts and epitelial cells

but latent infection of neurons• The primary target cell: mucoepitelial cells• Site of latency: neurons

Herpes simplex virus

• Means of spread: HSV-1 close contact, HSV-2 close contact+sexual transmission!

• Generally cause infection at the site of infection

• HSV-1: infections above the waist• HSV-2: infections below the waist• Growth characteristics are different• HSV-2 :more potential for viremia

           

                                                                                               

             

           

                                                                                              

              

Herpes simplex virus

• Initiates infection through mucosal membranes or breaks in the skin

• Virus replicates in the cells at the base of the lession and infects the innervating neurons

• Travels by retrograde transport to the ganglion( trigeminal ganglion for oral HSV, sacral ganglia for genital HSV)

Herpes simplex virus

• Then turns to initial site of infection• May be inapparent or vesicular( vesicle fluid

contains infectious virons)• Tissue damage: viral

pathology+immunopathology• Heals without a scar• Latent infection occurs in neurons

Herpes simplex virus

Infects most types of human cells, even cells of other species.

Lytic infection of fibroblasts and epitelial cells and latent infection of neurons

HSV-1 binds to heparan sulfate , a proteoglycan found on the outside of many cell types

Herpes simplex virus

Interacts HveC (herpes virus entry mediator C) : a member of immunoglobulin protein family similar to polio virus receptor, found on most cells and neurons

Penetrates by fusionDuring latent infection: the only region of genome to

be trancribed generates latency associated transcripts(LATs) and these RNAs are not translated in protein

Epidemiology

• Virus causes lifelong infection• Recurrent diseases is source of contagion• Asymtomatic shedding• Saliva, vaginal secretion, lesion fluid• Transmitted orally, sexually, into eye, breaks in skin• HSV-1 usually orally• HSV-2 usually sexually

Herpes simplex virus

• Recurrence: stress, trauma, fever, sunlight)• The virus travels back down the nerve causing

lessions at the dermatome• Recurrences are less severe and more

localized

• HSV-1 is common• 90% have antibody by 2 years of age• HSV-2 occurs later in life with sexual activity• Physicians,nurses,dentists at risk for infection of

fingers (herpetic whitlow)• Immunocompromised people and neonates at risk of

disseminated, life-threateneing disease.

Clinical Syndromes

• HSV-1 and HSV-2 are common human pathogens• Painful but benign manifestations and recurrent

disease• A clear vesicle on an erythematous base• Pustular lesion, ulcer, crusted lesion• Sinificant morbidity and mortality on infection of

eye,brain or on disseminated infection in immunosuppressed person or neonate.

Clinical Syndromes

• Primary herpetic gingivostomatitits• Recurrent mucocutaneous HSV(cold sores, fever

blister)• Herpes pharyngitis• Herpetic keratitis: corneal damage leading to

blindness• Herpetic whitlow• Eczema herpeticum• Genital herpes mostly by HSV-2

           

                                                                                                                                                                                      

                                    

Clinical Syndromes

-Herpes encephalitis: usually by HSV-1,the most common viral cause of sporodic encephalitis.Mortality is high.

At all age, at any time of year-HSV meningitis: complication of genital HSV-2-Neonatal infection: HSV-2, usually fatal

           

                                                                                        

                    

Neonatal HSV• HSV-2• Either during passage through genital tract• Or rarely in utero• Postnatally from family or hospital personel• Immune system weak• Disseminates to organs• Baby is septic and vesicular lesions• Death,or mental retardation or neurological

disability

Laboratory diagnosis

• Cytology and histology: Tzanck smear(scraping of the base of a lesion), Papanicolaou smear or biopsy specimen

• Cytopathic effects: syncytia, ballooning of cytoplasm, Cowdry A intranuclear inclusions

• Direct antigen detection: immunofluorescence method or immunoperoxidase method

• DNA :in situ hybridization or PCR in tissue or vesicle fluid

Laboratory diagnosis

• Virus isolation: CPE in 1-3 days in HeLa, Hep-2 cells, human embryonic fibroblasts and rabbit kidney cells. Isolates are identified by immunologic methods by antigen detection by IFA.

• Serology:primary infection, type specific antibody by ELISA (differentiates HSV-1 and HSV-2)

Approach Test/Comment

Direct microscopic examination of cells from base of lesion

Tzanck smear shows multinucleated giant cells and Cowdry type A inclusion bodies.

Cell culture HSV replicates and causes identifiable cytopathologic effect in most cell cultures.

Assay of tissue biopsy, smear, cerebrospinal fluid, or vesicular fluid for HSV antigen or genome

Enzyme immunoassay, immunofluorescent stain, in situ DNA probe analysis, and polymerase chain reaction (PCR).

HSV type distinction (HSV-1 vs. HSV-2) Type-specific antibody, DNA maps of restriction enzyme fragments, sodium dodecyl sulfate-gel protein patterns, DNA probe analysis, and PCR.

Serology Serology is not useful except for epidemiology.

Treatment

• Nucleotide analogues, viral DNA polymerase inhibitors

• Prevents or shortens the course of primary or recurrent disease

• Can not eliminate latent infection

Treatment

• Acyclovir• Penciclovir• Valacyclovir• Famciclovir• Adenosine arabinoside• Iododeoxyuridine• Trifluridine

FDA-Approved Antiviral Treatments for Herpesvirus Infections

Herpes Simplex 1 and 2 Acyclovir Penciclovir Valacyclovir Famciclovir Adenosine arabinoside Iododeoxyuridine Trifluridine Varicella-Zoster Virus Acyclovir Famciclovir Valacyclovir Varicella-zoster immune globulin Zoster immune plasma Live vaccine Epstein-Barr Virus None Cytomegalovirus Ganciclovir* Valganciclovir* Foscarnet* Cidofovir*

The

Pregnant women

• Active genital HSV• Asymtomatic shedding• Such transmission can be prevented by

cesarean section• No vaccine available yet.

Varicella-Zoster

• Chickenpox(varicella)• With recurrence :herpes zoster-shingles:zona• Primary target cell: mucoepitelial cell• Site of latency: neuron• Means of spread: respiratory and close

contact• Viremia occurs after local replication :skin

lessions over the entire body

Disease Mechanisms of Varicella-Zoster Virus (VZV)

Initial replication is in the respiratory tract. VZV infects epithelial cells, fibroblasts, T cells, and neurons. VZV can form syncytia and spread directly from cell to cell. Virus is spread by viremia to skin and causes lesions in successive crops. VZV can escape antibody clearance, and cell-mediated immune response is essential to control infection. Disseminated, life-threatening disease can occur in immunocompromised people. Virus establishes latent infection of neurons, usually dorsal root and cranial nerve ganglia. Herpes zoster is a recurrent disease; it results from virus replication along the entire dermatome. Herpes zoster may result from depression of cell-mediated immunity and other mechanisms of viral activation.

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Varicella-Zoster

• Primary VZV infection: mucosa of respiratory tract

• Viremia• Reticuloendotelial system,liver,spleen• 11-13 days later secondary viremia• Virus is spread through the body and

skin=rash+fever+systemic symptoms

           

                                                                                                

            

Varicella-Zoster

• Latent in dorsal root or cranial nerve ganglia after primary infection

• Reactivates in older adults and in patients with impaired immunity.

• On reactivation : a vezicular rash along the entire dermatome

• Children and leukemia: VZV more serious and more disseminated disease

Varicella-Zoster

• Extremely communicable• Rates of infection exceeds 90% among

household contact• Contagious before and during symptoms.• HZ develops in 10-20% of people infected with

VZV and contains viable virus.

Varicella(Chickenpox)

• Five classic childhood exanthems: chickenpox, measles, roseola, fifth disease,rubella

• Mild childhood disease• Fever+maculopapular rash• 14 days incubation• All stages of skin lesion (vesicle, pustular, crust)• More severe on trunk even on scalp• Bacterial superinfection

Varicella(Chickenpox)

• Severe in adults (interstitial pneumonia)• Severe in neonates and

immunocompromised.

Herpes-zoster

• Recurrence of latent varicella• Severe pain• Rash limited to the dermatome

           

                                                                                              

              

Varicella-Zoster

• Laboratory diagnosis:• Cytology• Virus isolation: difficult• Serology• Treatment:• ACV,famciclovir and valacyclovir• Prophylaxis: VZIG:varicella-zoster

immunoglobulin:immunosuppressed patients• A live attenuated vaccine(Oka strain)

Epstein-Barr Virus

• Heterophile antibody-positive infectious mononucleosis

• Chronic disease• Associated with endemic Burkitt’s lymphoma,

Hodgkin’s disease, nasopharyngeal carcinoma, B-cell lymphomas in patients with acquired or congenital immunodeficiencies.

• Hairy oral leukoplakia• Mitogen for B cells and immortalizes them

Epstein-Barr Virus

Gammaherpesvirinae:Primary target cell: B cells and epitelial cellsSite of latency: B cellMeans of spread: saliva (kissing disease)Limited host range and tissue tropism: receptor for C3d

component of the complement system (CR2 or CD21) which is expressed on B cells of humans and some epitelial cells of oro- and nasopharynx.

• Select viral genes are expressed, depending on the state of the B cell; they include Epstein-Barr nuclear antigens (EBNAs) 1, 2, 3A, 3B, and 3C; latent proteins (LPs); latent membrane proteins (LMPs) 1 and 2

• The EBNAs and LPs are DNA-binding proteins that are essential for establishing and maintaining the infection (EBNA-1), immortalization (EBNA-2), and other purposes.

• The LMPs are membrane proteins with oncogene-like activity. These proteins stimulate the growth of and immortalize the B cell.

• EBV establishes latency in memory B cells in which only the EBNA-1 and LMP-2 are expressed, maintaining the genome in the cells but with minimal potential for immune recognition of the infected cell.

Disease Mechanisms of Epstein-Barr Virus

•Virus in saliva initiates infection of oral epithelia and spreads to B cells in lymphatic tissue. •There is productive infection of epithelial and B cells. •Virus promotes growth of B cells (immortalizes). •T cells kill and limit B-cell outgrowth. T cells are required for controlling infection. Antibody role is limited. •EBV establishes latency in memory B cells and is reactivated when the B cell is activated. •T-cell response (lymphocytosis) contributes to symptoms of infectious mononucleosis. •There is causative association with lymphoma in immunosuppressed people and African children living in malarial regions (African Burkitt's lymphoma) and with nasopharyngeal carcinoma in China.

EBV

•The diseases of EBV result from either an overactive immune response (infectious mononucleosis) or

•the lack of effective immune control (lymphoma and hairy cell leukoplakia).

Epstein-Barr Virus

EBV activate B-cell growth and prevents apoptosis(programmed cell death)

T cell response (lymphocytosis) :atypical Lymphocytosis:Downey cells account for 10-80% of total white blood cells during the second week

Lymph glands,spleen and liver swellsMild in children

           

                                                                                         

                   

           

                                                                                               

             

Epstein-Barr Virus

Virus causes lifelong infectionMay cause aymptomatic sheddingRecurrent disease is a cause of contagionChildren:mild or asmptomaticTeenagers and adults: infectious mononucleosisImmunocompromised people: at high risk of for

life threatening neoplastic disease

Diagnosis of Epstein-Barr Virus

1.Symptoms a.Mild headache, fatigue, fever b.Triad: Lymphadenopathy, splenomegaly, exudative pharyngitis c.Other: Hepatitis, ampicillin-induced rash

2.Complete blood cell count a.Hyperplasia b.Atypical lymphocytes (Downey cells) (T cells)

3.Heterophile antibody (transient) 4.EBV-antigen specific antibody

• post-transplant lymphoproliferative disease• Many Hodgkin's lymphomas can also be

attributed to EBV • Hairy Oral Leukoplakia

           

                                                                                        

                    

EBV-associated neoplasms

• Geographic distribution• Co-factor?• Endemic Burkett’s lymphoma: Africa:malaria• Nasopharyngeal carcinoma: China

Laboratory diagnosis• Heterophile antibody: results from nonspecific activation of B

cells by EBV• IgM antibody recognizes Paul-Bunnell antigen on sheep, horse

and bovine erythrocytes not on guinea pig kidney cells• Detected at the end of first week , lasts for several months• Monotest, ELISA: specific antibodies• VCA-IgM, antibody to early antigen (EA): recent infection• VCA-IgG, EBNA: previous infection

Cytomegalovirus(CMV)

• Betaherpesvirnae: lymphotropic• Primary target cell: monocyte, lymphocte,

epitelial cell• Site of latency: monocyte, lymphocyte and?• Means of spread: close contact, transfusions,

tissue transplant and congenital

Sources of infection

• Neonate: transplacental transmission, intrauterine infection, cervical secretion

• Baby or child: body secretions, breast milk, saliva, tears, urine

• Adult: sexual transmission(semen), blood transfusion, organ graft

Clinical findings

• Predominant presentation: asymptomatic• Neonates: deafness, mental retardation• Immunosuppressed patients: disseminated

dissease, severe disease (pneumonia, retinitis, colitis, esophagitis)

CMV

• the most common viral cause of congenital defects

• particularly important as an opportunistic pathogen in immunocompromised patients

Congenital infection

• An important cause of congenital disease• Serious birth defects is high if primary infection

occurs during pregnancy• Microcephaly, intracerebral

calcification,hepatosplenomegaly,rash(cytomegalic inclusion disease), unilateral or bilateral hearing loss, mental retardation

• CMV in the urine in the first week (culture,PCR)

CMV immunsupressed patients

• CMV disease of the lung (pneumonia and pneumonitis) is a common outcome in immunosuppressed patients

• Retinitis (%10-15 AIDS patients)• Interstitial pneumonia and encephalitis • colitis or esophagitis may develop in as many as

10% of patients with AIDS• May be related with GVHR after bone marrow

transplantation

Table 54-6. Cytomegalovirus Syndromes

Tissue Children/AdultsImmunosuppressed Patients

Predominant presentation

Asymptomatic Disseminated disease, severe disease

Eyes - Chorioretinitis

Lungs - Pneumonia, pneumonitis

Gastrointestinal tract

- Esophagitis, colitis

Nervous system

Polyneuritis, myelitis Meningitis and encephalitis, myelitis

Lymphoid system

Mononucleosis syndrome, post-transfusion syndrome

Leukopenia, lymphocytosis

Major organs Carditis,* hepatitis* Hepatitis

Neonates Deafness, intracerebral calcification, microcephaly, mental retardation

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. Epidemiology of Cytomegalovirus Infection

Disease/Viral Factors •Virus causes lifelong infection. •Recurrent disease is source of contagion. •Virus may cause asymptomatic shedding. Transmission •Transmission occurs via blood, organ transplants, and all secretions (urine, saliva, semen, cervical secretions, breast milk, and tears). •Virus is transmitted orally and sexually, in blood transfusions, in tissue transplants, in utero, at birth, and by nursing. Geography/Season •Virus is found worldwide. •There is no seasonal incidence. Who Is at Risk? •Babies. •Babies of mothers who experience seroconversion during term: At high risk for congenital defects. •Sexually active people. •Blood and organ recipients. •Burn victims. •Immunocompromised people: Symptomatic and recurrent disease. Modes of Control •Antiviral drugs are available for patients with acquired immune deficiency syndrome. •Screening potential blood and organ donors for cytomegalovirus reduces transmission of virus.

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Laboratory tests

• Cytology and histology: ‘OWL’s eye’ inclusion body basophilic intranuclear:Urine not so sensitive

• Antigen in peripheral leucocytes• DNA by PCR• Cell culture: Human diploid fibroblasts• Serology: primary infection

Treatment

• Ganciclovir• Foscarnet• Valganciclovir• Cidofovir• No vaccine

Other mononucleosis causes

• EBV• CMV• HIV• Toxoplasma gondii

Human herpesvirus 6

• Betaherpesvirinae• Lymphotropic , ubiquitous • Primary target cell: T cells and ?• Site of latency: T cells and ?• Means of spread: Respiratory, close contact• Exanthema subitum: roseola• A mononucleosis syndrome and lympadenopathy

Exanthema subitum

• High fever+rash for 24-48 hours• Incubation 4-7 days• Recovery without complication

Human herpesvirus 8

• HHV-8 DNA sequences were discovered by PCR in biopsy specimens of

• Kaposi’s sarcoma (characteristic opportunistic diseases associated with AIDS)

• Primary effusion lymphoma (rare type of B-cell lymphoma)

• Multicentric Castleman’s disease

Human herpesvirus 8

• Kaposi’s sarcoma-related virus• Primary target cell: Lymphocyte and other

cells• Site of latency:?• Means of spread: close contact, sexual, saliva?• Limited to certain geographic areas (Italy,

Greece, Africa) and AIDS

Human herpesvirus 8

• Laboratory diagnosis:• Serology: specific antibodies:IFA IgG,IgM• HHV-8DNA by PCR

Herpesvirus simiae(B virus)

• Asian monkeys• Bites, saliva• Encephalopathy in humans• fatal