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Medical Microbiology Herpesvirus I and II Fall, 2009

Medical Microbiology Herpesvirus I and II Fall, 2009 INSTRUCTOR: Dr. J. David Gangemi OBJECTIVE: Introduction to virus biology, pathogenesis, disease characteristics, prevention and treatment REFERENCE: Murray, 6th Edition, Chapter 54

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Medical Microbiology Herpesvirus I and II Fall, 2009

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  1. Medical Microbiology Herpesvirus I and II Fall, 2009 INSTRUCTOR: Dr. J. David Gangemi OBJECTIVE:Introduction to virus biology, pathogenesis, disease characteristics, prevention and treatment REFERENCE:Murray, 6th Edition, Chapter 54

  2. OUTLINE OF MAJOR TEACHING POINTS I. Background II. Classification III. Immune Response to Infection IV. Neurovirulence and latency V. Treatment and Control VI. Disease

  3. From the Greeks…... Hippocrates “Herpes”…..to creep or crawl. Term used to describe the spreading nature of skin lesions.

  4. William Shakespear….Romeo and Juliet From Queen Mab, the midwife of the fairies…. “O’er ladies lips, who straight on kisses dream, which oft the angry Mab with blisters plagues, because their breaths with sweetmeats tainted are”

  5. I. Background 25 viruses in the family Herpetoviridae- a number of these are known to infect man: • herpes simplex virus (HSV) • Epstein-Barr virus (EBV) • cytomegalovirus (CMV) • varicella-zoster virus (VZV) • human herpes 6 & 7 (exanthum subitum & roseola infantum) • HHV 8 (Kaposi’s sarcoma-associated).

  6. II. Classification

  7. III. Immune Response to HSV Infection Humoral Antibody: • Neutralization of infectious virus • Complement-mediated lysis of infected cells • Present in mothers milk CMI: In recovery from herpetic infections, the cellular arm of the immune response appears to have the greater role (agammaglobulinemics recover from infection if they have normal T cell functions) Also Important: Interferon, cytotoxic T-lymphocytes, NK cells and macrophages in acute and in recurrent infections

  8. IV. Neurovirulence and Latency in HSV and VZV Herpes simplex and varicella zoster viruses have two unique biologic properties that influence human disease……. the capacity to invade and replicate in the CNS and the capacity to establish a latent infection. • Virus lies dormant for a period of time but may become reactivated even in the presence of neutralizing antibodies. • Most studies indicate that the sensory ganglia are the source of virus that produces recurrent skin lesions--trigeminal ganglia in type 1 and sacral ganglia in type 2.

  9. Neurolatency Hypothesis Dynamic state-- persistence of low levels of infectious virus in sensory ganglia, neurons may or may not killed retrograde vs anterograde transport of virus through peripheral sensory nerve endings Static state -- DNA of virus is maintained in a non-replicating state at some extrachromosomal site in neuron or is integrated into cellular DNA

  10. Maintenance of Herpesvirus Genome and Latency Activated Transcripts

  11. V. Treatment and Control Chemotherapy: HSV and VZV….acycloguanosine (acyclovir) and prodrugs valacyclovir and famciclovir (famciclovir is prodrug of penciclovir) CMV…ganciclovir; phosphonoacetate, interferon Agents that inactivate: ethyl ether, chloroform, glutaraldehyde; phototherapy with neutral red Immunologic approaches: vaccination with live attenuated virus for chickenpox (varicella-zoster); experimental live virus and HSV subunit vaccines (in development)

  12. VI. DISEASE

  13. Primary and Recurrent HSV Infections Primary infection with HSV-1 or HSV-2 virus may result in latency--that is, the virus goes into a dormant existence in which no clinical features are apparent. However, with an appropriate stimulus such as sunlight, fever, menstration, or emotional stress, the virus may reactivate and produce disease sequelae. Note-Both primary infections with HSV and endogenous recurrences may be asymptomatic and produce immune responses without overt clinical signs and symptoms

  14. Clinical Course HSV-2

  15. HSV Disease • HSV isolated from lesions occurring above the waistline is usually type 1 and HSV isolated from sites below the waistline is usually type 2.Nonetheless, because of oral-genital contact, either type of virus may be found in either location. • Primary HSV-1 infections are most common in childhood. The usual manifestation in young children is gingivostomatitis; in adolescents it is tonsillitis or pharyngitis. • The prevalence of genital herpes bears a strong relationship to sexual promiscuity. Genital HSV-2 infections are on the increase and are now second in frequency only to gonorrhea. Unfortunately, one can have both humoral and cellular immunity to HSV-1 and still contract HSV-2. Genital or nongenital herpes can occur in the same person, at the same time or sequentially.

  16. HSV Disease:Primary Infections • 1. Gingivostomatitis -- affects children 1-6 years old. No seasonal distribution. Accompanied by fever and sore mouth. • 2. Vulvovaginitis -- involves mucous membranes and skin of the labia and lower vagina. Ulcers are accompanied by fever and regional lymphadenopathy. In males- herpes progenetialis. • 3. Meningoencephalitis -- may result from a primary infection of the CNS; however, in some instances, illness follows viral recurrence in individuals with pre-existing antibodies. • 4. Keratoconjunctivitis -- corneal ulcerations induced by herpesvirus may be quite deep and can result in blindness.

  17. HSV Disease:Primary Infections • 5. Eczema herpeticum- complication of eczema or sever atopic dermatitis. The abraded weeping and denuded skin is inoculated with virus which spreads widely in the absence of the protective cornified epithelium. • 6. Burn injury- involvement of abraded and injured skin -- may be quite severe. • 7. Neonatal disease- disseminated, visceral and congenital infections…fetus is at risk when mother is shedding virus in birth canal.

  18. HSV Disease:Recurrent Infection Cold sores (labialis) Genital lesions (herpes genitalis) Keratoconjunctivitis Encephalitis Meningoencephalitis

  19. Other Herpesviral Diseases 1. Varicella(chickenpox): Usually mild disease (except in immunosuppressed) with characteristic rash and pox formation. Begins as respiratory infection then disseminates. 2. Herpes Zoster (shingles): Reactivation of latent varicella virus…..cause of reactivation unknown. 3.Cytomegaloviruses(CMV): A ubiquitous virus shed persistently by infected hosts...disease in those with abnormal CMI. Is responsible for a form of mononucleosis which is heterophile negative. 4. Epstein-Barr virus (EBV): Etiologic agent of infectious mononucleosis which is heterophile positive.

  20. NEJM June 2, 2005: Vol 352 NO. 22

  21. *Other members of the Shingles Prevention Study Group are listed in the Appendix

  22. Aging, Immunity, and the Varicella-Zoster Virus Ann Arvin, M.D. NEJM June 2, 2005: Vol 352 NO. 22

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