HERPES VIRUS

Herpesvirus Architecture envelope tegument capsid DNA L. Henderson, NCI

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Herpesvirus infections are common… healthy children healthy 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

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

HSV Infections 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 *Other (usually immune compromised): tracheobronchitis, pneumonia, epiglottitis, esophagitis, colitis, hepatitis, retinitis

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

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

Herpes gladiatorum

Whitlow

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

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

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

Genital HSV Burden of disease: Viral “shedding” 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)

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

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

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

HSV Diagnosis Serology PCR (CSF) 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

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

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

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

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)

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

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)

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

CMV Disease in Immunocompromised 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

Normal CMV Retinitis

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

CMV Intranuclear Inclusions Owl’s eye cell

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

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)

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

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

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

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+)

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

Chickenpox, Varicella Zoster HSV-1 Cold sore