MIC301 HERPESVIRIDAE (herpes, chickenpox, shingles, mono, etc.) Thomas Melendy, Ph.D. [email protected] PresentationSlide 3Slide 4Slide 5Slide 6Slide 7HERPESVIRIDAE HSV-1 & HSV-2Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21HERPESVIRIDAE VZVSlide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29HERPESVIRIDAE EBVSlide 31Slide 32Slide 33Slide 34Slide 35HERPESVIRIDAE CMVSlide 37Slide 38Slide 39Slide 40HERPESVIRIDAE recently discovered HHVs HHV6, HHV7, & HHV8Slide 42Slide 43Slide 44Slide 45MIC301HERPESVIRIDAE (herpes, chickenpox, shingles, mono, etc.)Thomas Melendy, [email protected]://graphics8.nytimes.com/images/2010/05/26/health/consults26/consults26-blogSpan-v3.jpg•Major feature of pathogenesis is that these viruses establish latent infections.•Following an initial infection (primary), the virus establishes itself in a non-infectious form in neural or lymphoid tissues, and can reactivate to give a secondary (recurrent) infection which is often the major cause of disease.•Ubiquitous infections – Most individuals are infected with five of the eight human herpesviruses.Herpesvirus genomeshttp://www.ncbi.nlm.nih.gov/books/NBK47439/figure/c02pkk-y6y-sp5-rs8/?report=objectonly(HSV-2)(HHV-7)http://www.dbc.uci.edu/~faculty/wagner/hsvimg04z.jpgHERPESVIRIDAEHSV-1&HSV-2Infection Cycle of Herpes Simplex VirusHerpes Simplex Type 1 recurrent infection.HSV-1 Induced KeratitisSecond only to trauma as a cause of corneal blindness in the U.S.Herpes GladiatorumHerpes GladiatorumNEONATAL HSV INFECTION• Contracted during passage through the genital canal.• Contracted postnatally from individuals shedding virus.• Disseminated HSV infection to major organs and CNS.• Progression of infection to CNS results in death, mental retardation or neurologic disability even with treatment. 80% mortality in the absence of antiviral therapy.Neonatal Herpes Simplex Type 2Activation of AcyclovirOHVal-ValacyclovcirValine results in greater bioavailability.AraA is used in the treatment of HSV encephalitis.Trifluridine and Iododeoxyuridine are used in the treatment of HSV keratitis.HERPESVIRIDAEVZVPathogenesis of Primary Varicella InfectionVaricella rash in all stages of evolution.VZV Latency and ReactivationThoracic Dermatome Cranial DermatomeHerpes Zoster (Shingles)Consequences of Varicella infection during pregnancyAcyclovir and ValacyclovcirEffective vaccines against varicella and zoster are available and in use.VZV Intervention StrategiesLymphotropic HerpesvirusesViruses which infect cells of the lympho-reticular system: T cells, B cells, monocyte/macrophages, dendritic cells. EBV, CMV, HHV6, HHV7, HHV8HERPESVIRIDAEEBVEpstein Barr Virus PathogenesisBurkitt’s Lymphoma Nasopharyngeal CarcinomaEpstein Barr Virus PathogenesisOral Hairy LeukoplakiaAIDS-Related EBV SyndromeEPSTEIN BARR VIRUS AND TRANSPLANTATION• Post transplant lymphoproliferative disease• Bone marrow and solid organ transfers• EBV transferred in graft• EBV infects recipient B cells• Recipient EBV seronegative and under high levels of immunosuppressionHERPESVIRIDAECMVCytomegalovirus1. Associated with monocytes, polymorphonuclear leukocytes and macrophages (also immune cells, but not B/T cells).2. Primarily peri-natal and venereal transmission.3. Most infections in the normal host are asymptomatic or mild. 4. Spread by close contact. Present in virtually all human body fluids. Virus shed in saliva, tears, urine, semen and vaginal secretions.5. Populations at risk: embryos, neonates and immunocompromised individuals, including transplant recipients. CMV is the major cause of deafness and hearing loss in children.6. CMV in the immunocompromised host: pneumonitis (as high as 17% in bone marrow transplants), retinitis, colitis and esophagitis (6-30% in AIDS patients).7. Gancyclovir is the current drug of choice.8. A combination vaccine is under development and shows considerable promise in a mouse model.Activated by CMV UL 97 kinaseEffective for treatment of CMV retinitis, esophagitis colitis and pneumoniaHERPESVIRIDAErecently discovered HHVsHHV6, HHV7, & HHV8HHV6 and HHV7 HHV6 is associated with roseola or exanthem subitum in children. It may be involved in neutropic and lymphoproliferative diseases in adults upon reactivation. HHV6 can infect both T and B lymphocytes. There is also evidence of synergy with reactivation of cytomegalovirus. Two sub-types, HHV6-A and HHV6-B have been identified:HHV6-B is the causative agent of roseola and is most frequently recovered from individuals having bone marrow transplants. Both are associated with encephalitis. HHV6-A may be more neuroinvasive.In one study, 2% of AIDS patients had HHV6 in cerebrospinal fluid. The HHV-6 genome has been shown, in rare cases, to integrate into the human genome. Thus it can spread vertically as well as horizontally HHV7 has not yet been associated with any human disease. The virus can infect T cells. It, like the other lymphotropic herpesviruses, is becoming a concern in the context of organ transplant recipients and donors.Kaposi’s SarcomaHHV 8HHV8 - Kaposi Sarcoma Herpesvirus HHV8 was identified as a new herpesvirus about fifteen years ago using recombinant DNA techniques. It is a member of the gamma herpesvirus family. HHV8 is the infectious agent responsible for Kaposi's sarcoma (KS). Present in tissues obtained from: Classical Mediterranean KS, Endemic KS (sub-Saharan Africa), KS associated with AIDS and post-transplant (iatrogenic) KS. KS is the most common neoplasm in homosexual and bisexual men. Dual seropositives run as high as 30%. The virus has also been associated with Castleman's Disease, primary effusion lymphoma, and body cavity lymphoma.In endemic countries, HHV8 is transmitted in early childhood (18-24 months of age). Classical KS occurs more frequently in men. This is not mirrored in sero-prevalence which is almost equal male/female. AIDS-related KS/HHV8 can be sexually transmitted although there is little virus in semen. Orogenital sex appears to be a risk factor due to readily detectable levels in the saliva of sero-positive individuals. HHV8 has been associated with deaths in cases of seronegative organ recipients receiving transplants from individuals with latent HHV8 infections and in seropositive recipients due to reactivation of the virus during immunosuppressive therapy. Antiviral therapy includes use of acyclovir and