1. HERPES VIRUS

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

4. g a b

5. Herpesvirus infections are common…
healthy children healthy adults
HSV % %
HSV % %
VZV % %
EBV % %
CMV % %
HHV % %
HHV % %
HHV <3% %
adapted from Straus SE in Principles and Practice of Infectious Diseases, 2005

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

7. 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

8. 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

9. 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

10. Herpes gladiatorum

11. Whitlow

12. 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

13. 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

14. 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

15. 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)

16. 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

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

18. 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

19. 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

20. 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

21. 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

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

23. 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)

24. 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

25. 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)

26. 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

27. 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

28. Normal
CMV
Retinitis

30. 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

31. CMV Intranuclear Inclusions
Owl’s eye cell

32. 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

34. 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)

35. 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

36. 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

37. 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

38. 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+)

39. 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

40. Chickenpox, Varicella Zoster
HSV-1 Cold sore