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Human Herpesviruses

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-1 Human herpesvirus 2 Herpes simplex type 2 HSV-2

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Human Herpesviruses

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  1. Human Herpesviruses

  2. Human herpesviruses • Three subfamilies (genome structure, tissue tropism, cytopathologic effect, site of latent infection) • Alphaherpesvirinae: Human herpesvirus 1 Herpes simplex type 1 HSV-1 Human herpesvirus 2 Herpes simplex type 2 HSV-2 Human herpesvirus 3 Varicella-zoster virus VZV • Gammaherpesvirinae Human herpesvirus 4 Epstein-Barr virus EBV Human herpesvirus 8 Kaposi’s sarcoma related virus HHV-8 • Betaherpesvirinae Human herpesvirus 5 Cytomegalovirus CMV Human herpesvirus 6Herpes lymphotropic virus HHV-6 Human herpesvirus 7 Human herpesvirus 7 HHV-7

  3. 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.

  4. 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

  5. Body_ID: T054001

  6. icosadeltahedral capsid and an envelope

  7. 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

  8. 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

  9. 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

  10. 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)

  11. 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

  12. 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

  13. 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 fusion During latent infection: the only region of genome to be trancribed generates latency associated transcripts(LATs) and these RNAs are not translated in protein

  14. 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

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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)

  23. Body_ID: T054002 Body_ID: None

  24. Treatment • Nucleotide analogues, viral DNA polymerase inhibitors • Prevents or shortens the course of primary or recurrent disease • Can not eliminate latent infection

  25. Treatment • Acyclovir • Penciclovir • Valacyclovir • Famciclovir • Adenosine arabinoside • Iododeoxyuridine • Trifluridine

  26. Pregnant women • Active genital HSV • Asymtomatic shedding • Such transmission can be prevented by cesarean section • No vaccine available yet.

  27. 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

  28. 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

  29. 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

  30. 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.

  31. 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

  32. Varicella(Chickenpox) • Severe in adults (interstitial pneumonia) • Severe in neonates and immunocompromised.

  33. Herpes-zoster • Recurrence of latent varicella • Severe pain • Rash limited to the dermatome

  34. 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)

  35. 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

  36. Epstein-Barr Virus Gammaherpesvirinae: Primary target cell: B cells and epitelial cells Site of latency: B cell Means 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.

  37. 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.

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