HERPES VIRUS
Herpesviruses
Sub -fa mil y
Gro w th
Cyc le
La t e nt
In f e ctio n s
Ge n us
Sys te mat i c
Nam e
Com mon
Nam e
A lp haherpesv irus
Sh ort
Neur on s
Si m pl exvir us
Si m pl exvir us
Va r ice ll ov irus
HHV-1
HHV-2
HHV-3
H SV-1
H SV-2
VZ V
Be t a her pe sv irus
Lo n g
Gla nd s ,
k id ney ,
Ma c roph ages
Cy t om e gal ov irus
R os e olo vir us
R os e olo vir us
HHV-5
HHV-6
HHV-7
HCM V
HHV-6
HHV-7
Gam ma herpesv irus
Va r ia bl e
Lym phoid
t is s ue
Lym pho cr y pt ov ir us
R ha dino vir us
HHV-4
HHV-8
EBV
K SH V
Herpesvirus Architecture
envelope
tegument
capsid
DNA
L. Henderson, NCI
g
a
b
Herpesvirus infections are common…
HSV1
HSV2
VZV
EBV
CMV
HHV6
HHV7
HHV8
healthy children
20-40%
0-5%
50-75%
10-30%
10-30%
80-100%
40-80%
<3%
healthy adults
50-70%
20-50%
85-95%
80-95%
40-70%
60-100%
60-100%
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%)
Recurrences:
• duration of lesions about 10 days
• pain (98%)
• lesions more often unilateral
• dysuria (63%)
• 25% completely asymptomatic
• tender adenopathy (80%)
• 50% who have symptoms have
prodrome of tingling/pain
• duration of lesions: 2-3 weeks
• Lesions more often bilateral
• HSV isolated from urethra/cervix
in 80+% of patients
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:
– 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
Meningoencephalitis (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 highrisk 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