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