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HERPES VIRUS
tegument
envelope
capsid
DNA
Herpesvirus Architecture
L. Henderson, NCI
KSHVHVS
EBV
CMV
HSV-1HSV-2
Burkitt's lymphomaNasopharyngeal
carcinoma
Kaposi's sarcomaPrimary effusion lymphomaT cell lymphoma
VZVHHV6
HHV7
PhylogenyDK10/97
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
HSV1Mucosal
– Gingivostomatitis– Pharyngitis– Genital (10-15%)
Eye– Keratitis– Blepharitis/conjunctivitis
Skin– Painful vesicles– erythema multiforme
CNS– encephalitis– Bells palsy
HSV2Mucosal
– 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
Fever
Malaise
Myalgias
Difficulty eating
Cervical adenopathy
Exudative or ulcerative pharyngitis
Palate, tongue, buccal mucosa or gingiva may be involved
Duration 3-14 days
Primary Oral-Facial HSV
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/cervixin 80+% of patients
Recurrences: • duration of lesions about 10 days
• lesions more often unilateral
• 25% completely asymptomatic
• 50% who have symptoms haveprodrome 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 HSVBurden 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)
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– 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:
1) 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
CMVRetinitis
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
HSV-1 Cold sore
Chickenpox, Varicella Zoster