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HERPES VIRUS

HERPES VIRUS. Herpesvirus Architecture. envelope. tegument. capsid. DNA. L. Henderson, NCI. g. a. b. Herpesvirus infections are common…. healthy children healthy adults HSV1 20-40% 50-70% HSV2 0-5% 20-50% VZV 50-75% 85-95%

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HERPES VIRUS

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  1. HERPES VIRUS

  2. Herpesvirus Architecture envelope tegument capsid DNA L. Henderson, NCI

  3. g a b

  4. Herpesvirus infections are common… healthy childrenhealthy adults HSV1 20-40% 50-70% HSV2 0-5% 20-50% VZV 50-75% 85-95% EBV 10-30% 80-95% CMV 10-30% 40-70% HHV6 80-100% 60-100% HHV7 40-80% 60-100% HHV8 <3% 5-10% adapted from Straus SE in Principles and Practice of Infectious Diseases, 2005

  5. Herpesviruses • Large, double stranded DNA viruses • Transmission by close contact • exception - VZV (aerosol) • Latent (quiescent) and lytic (replicative) cycles • Specific tissue tropism

  6. HSV1 Mucosal Gingivostomatitis Pharyngitis Genital(10-15%) Eye Keratitis Blepharitis/conjunctivitis Skin Painful vesicles erythema multiforme CNS encephalitis Bells palsy HSV2 Mucosal Gingivostomatitis Pharyngitis Genital Skin Painful vesicles erythema multiforme CNS meningitis Bells palsy HSV Infections *Other (usually immune compromised): tracheobronchitis, pneumonia, epiglottitis, esophagitis, colitis, hepatitis, retinitis

  7. Herpes simplex - Primary Infection • Infection by direct contact and viral entry via mucous membranes or keratinized layer of skin • Incubation period 2-8 days • Systemic symptoms may occur (fever, malaise, myalgias) • Skin/systemic symptoms resolve within one week, although cervical LN enlargement may take longer *** many infections are asymptomatic

  8. Primary Oral-Facial HSV Fever Malaise Myalgias Difficulty eating Cervical adenopathy Exudative or ulcerative pharyngitis Palate, tongue, buccal mucosa or gingiva may be involved Duration 3-14 days

  9. Herpes gladiatorum

  10. Whitlow

  11. Genital Herpes Infections • Transmission via the genital mucosa • Latency in sacral ganglia • 85-90% HSV-2 • transmission to discordant partners: • 50-75% of genital HSV acquired from an • asymptomatic partner • mean of about 4 months • rate of about 10% per year • easier for women to acquire from men

  12. Genital Herpes: Clinical Features • Primary disease: • systemic symptoms (70%) • pain (98%) • dysuria (63%) • tender adenopathy (80%) • duration of lesions: 2-3 weeks • Lesions more often bilateral • HSV isolated from urethra/cervix • in 80+% of patients • Recurrences: • duration of lesions about 10 days • lesions more often unilateral • 25% completely asymptomatic • 50% who have symptoms have • prodrome of tingling/pain

  13. Genital Herpes: Other Features • HSV-1 less often symptomatic • meningitis in up to 8% (usually HSV-2) • distant skin lesions (20%) • bladder dysfunction (2%) • proctitis (usually MSM) • higher rates of meningitis and urinary • retention in women • women more often culture positive

  14. Genital HSV Burden of disease: • in the US ~ 45 million infected • No correlation with race, geography, education, marital or socioeconomic status Viral “shedding” • occurs intermittently • more virus shed with active/symptomatic lesions or with immune suppression (may increase HIV acquisition) • shedding occurs on 1-8% of days with no lesions by culture (up to 28% of days by PCR) • Reduced with antivirals (to about 3% of days by PCR)

  15. Genital HSV • 88-92% of seropositive people do not recognize that they are infected • Primary/secondary prevention with antiviral medication is effective (later) • HSV2 disease increases HIV acquisition risk approx 3-fold

  16. HSV Diagnosis • Clinical clues (pain, same site of past recurrence) • Tzanck prep • ~65% sensitivity and specificity • Multinucleated giant cells with intranuclear inclusions

  17. HSV Diagnosis • Culture (fresh ulcer or vesicle) • 25-50% sensitivity overall, 90% if done within 48h • 100% specificity • Takes 24-48h to achieve cytopathic effect in culture • Immunofluorescence • Helpful for tissue specimens

  18. HSV Diagnosis • Serology • Sensitivity and specificity >90% • IgM not useful – does not distinguish between acute infection and recurrence • IgG conversion may take 6 months • PCR (CSF) • >95% sensitivity and specificity

  19. Herpes simplex - establishment of latency Following primary infection: • local replication in dermis/epidermis (responsible for symptoms of primary infection) 2) entry into neurons (sensory or autonomic) • intra-axonal transport to nerve cell bodies in ganglia • neural replication • centrifugal migration via sensory nerves • latency

  20. Herpes simplex - risk factors for reactivation • (multiple recurrences/severe disease) • HIV • chemotherapy • Transplant (70%) • Skin disease • Burns • Steroids • Pregnancy (oral/genital lesions) • Sunlight • Fever • Menstruation • Stress • Trauma

  21. Neurologic Disease and HSV • encephalitis (HSV1) • Mollaret’s syndrome • meningitis (HSV2) • Bell’s palsy • Autonomic dysfunction

  22. HSV Encephalitis • Primary infection with entry via olfactory tract • Extension from trigeminal or other cranial nerve ganglia via nerves passing through middle cranial fossa • Most cases thought to represent reactivation of virus from sites of latency in the CNS • HSV PCR in CSF: • sensitivity 98% (false neg if <4 days from sx onset)

  23. Cytomegalovirus (CMV) • Majority of population infected by age 40 (>75%) • Viral shedding from respiratory and urinary tract • Routes of transmission: sexual, close contacts, transfusion, organ transplant, perinatal

  24. Cytomegalovirus (CMV) Cell targets of infection: • hematopoietic cells (mononucleosis) • Intestinal epithelium (esophagitis/colitis) • endothelial cells (organ transplant rejection) • Renal epithelial cells (renal failure) • Salivary gland epithelium (parotitis) • Cardiac myocytes (heart failure) • Hepatocytes (hepatitis) • Dorsal root ganglia (polyradiculopathy)

  25. CMV mononucleosis • fever • pharyngitis, rash, lymphadenopathy and splenomegaly less common than with EBV • Heterophile antibody negative • Hepatitis (granulomatous), hemolytic anemia, thrombocytopenia more often than EBV

  26. AIDS Retinitis Colitis Esophagitis Cholangitis Polyradiculopathy Pneumonia Meningo-encephalitis (less severe vs HSV) Organ transplant Pneumonia Hepatitis Fever myocarditis GVHD ***Disease usually occurs in transplanted organs CMV Disease in Immunocompromised

  27. Normal CMV Retinitis

  28. CMV: Diagnosis • Culture – tissue, urine • Antibody testing • Risk assessment prior to organ transplantation • qPCR for CMV DNA (>1000 copies/ml = CMV disease in immune compromised) • Pathology-intranuclear inclusions

  29. CMV Intranuclear Inclusions Owl’s eye cell

  30. HHV-6 (roseola) • Probable transmission through saliva • Infects T cells and manipulates cytokine signaling • Clinical Features • Fever + rash (“sixth disease” or roseola infantum, often biphasic illness - fever precedes the onset of the rash; at the time the rash appears the child is afebrile) • Febrile seizures • Mononucleosis • Rare – encephalitis, hepatitis, myocarditis • Infections during immune suppression • HIV • Organ transplantation • Multiple sclerosis

  31. HHV-7 • Probable transmission through saliva, cervical secretions and breast milk • >95% of adults are seropositive • Replicates in CD4+ T cells and manipulates cytokine signaling • Clinical Features • Fever + rash (exanthem subitum) • Febrile seizures • Mononucleosis • Rare – neurologic disease, hepatitis, myocarditis • Immunosuppression • Organ transplantation (marrow suppression)

  32. Herpesvirus Infections: antiviral tx Acyclovir/famciclovir • converted by herpesvirus thymidine kinase to monophosphate • converted by cellular enzymes to dGTP analog which inhibits viral DNA polymerase • Useful for HSV, VZV infections Ganciclovir • converted by CMV phosphotransferase to monophosphate • converted by cellular enzymes to triphosphate • Competitively inhibits dGTP incorporation and viral DNAp Cidofovir • dCTP, converted by cellular enzymes to active triphosphate which inhibits DNA polymerase - thymidine kinase independent Foscarnet • competitive inhibitor of DNA polymerase

  33. Herpesvirus Infections: antiviral tx Valyl (valine) esters: • Prodrugs of acyclovir and ganciclovir • Valacyclovir • Valganciclovir • Confer approx 50% greater bioavailability • Converted to active drug after rapid first-pass metabolism in intestine/liver • Allow for longer dosing interval

  34. HSV: Utility of antivirals Acyclovir or Valacyclovir • Reduces pain, decreases viral shedding and speed healing of primary genital HSV • Effectively suppresses recurrent HSV (up to 80% reduction in recurrences) • Reduces, but does not eliminate, asymptomatic HSV shedding • Reduces transmission horizontally and vertically • Improves morbidity and mortality outcomes in HSV encephalitis • Prevents HSV infection in patients receiving chemotx or organ transplants (from about 70% to 5% of patients) • May reduce HIV transmission

  35. CMV: Utility of antivirals Ganciclovir or Valganciclovir • Effective for reducing replication and controlling progression of CMV disease during immune suppression (transplant, HIV) • No clear data for improved outcomes in immune competent patients • Effective for prevention of CMV disease in high-risk transplant recipients (D+/R-) or (D+/R+)

  36. HHV6/7: Utility of antivirals • IC50 for acyclovir or ganciclovir too high • Cidofovir reasonable if convincing clinical disease and withdrawal of immune suppression is not feasible

  37. Chickenpox, Varicella Zoster HSV-1 Cold sore

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