HerpesvirusesChapter 33

Properties of HerpesvirusesStructure and CompositionSpherical iscoahedron, 150-200 nmDouble-stranded DNA, linearMore than 35 proteinsEnvelopedReplication from nucleus (budding)FeaturesEncode many enzymesEstablish latent infectionsLifelong persistenceSignificant cause of death in immunocompromised hostsSome can cause cancers

Properties of HerpesvirusesClassification (human viruses)SubfamiliesAlphaBetaGammaSpeciesSimplex 1 (HHV-1) (alpha)Simplex 2 (HHV-2) (alpha)Varicella (HHV-3) (alpha)Epstein-Barr (HHV-4) (gamma)Cytomegalovirus (HHV-5) (beta)HHV-6 (beta)HHV-7 (beta)Kaposis sarcoma virus (HHV-8) (gamma)

Properties of HerpesvirusesReplication of HSVVirus attachment and membrane fusionViral host shutoff (VHS) protein released into the cytoplasm and initiates the degradation of host cell mRNA-Trans-inducing factor (TIF) is transported to the nucleusCapsid travels to nucleus where viral DNA is released, enters a nuclear pore and circularizesTIF induces the expression of viral alpha genes The mRNAs for the alpha genes are translated on ribosomesThe proteins then enter the nucleus and express the viral beta genesThe beta proteins are involved in degrading cellular chromatin and localizing cellular DNA to the inner side of the nuclear envelope (margination)Viral DNA is replicated as concatemersGamma proteins (structural) are expressedCapsid proteins self assemble and DNA concatemers are cleaved and packaged into capsids

Properties of HerpesvirusesReplication of HSV (cont.)Nuclear escapeViral proteins induce budding of the capsid through both nuclear membranesThus, capsid escapes into the cytoplasmViral proteins associate with the cellular vesiclesThese proteins have affinity for the capsid proteins and cause the vesicle to wrap around the virus, providing it with an double-layered envelopeVirus traverses the ER then Golgi prior to release from the cellThe outer membrane fuses with the plasma membraneThis permits the virus to leave the cell while retaining the inner membrane

Herpesvirus DiseasesHerpes Simplex virusesTwo speciesHSV-1: oropharyngeal sores (children)HSV-2: genitalia (young adults)Highly similar genomes, but distinct150 kb70+ polypeptidesVirulence factorsgC binds complement C3bgE is an Fc receptor for IgG

Herpes simplex viruses (cont.)PathologyWide cellular tropismMost common to dermal tissues (herpetic lesions)Cell fusion followed by cell lysisInflammatory responseTransmissionGenerally through direct contact with person shedding virusSome people shed virus despite absence of lesionsVirus enters through mucosal tissues; cannot penetrate healthy skinLatent infectionsVirus sequesters in nerve tissues (immunoprivileged site)HSV-1 in trigeminal gangliaHSV-2 in sacral gangliaVery few genes are expressed by infected cellsNo immune response against infected cellsHerpesvirus Diseases

Herpes simplex viruses (cont.)Clinical conditionsOropharangeal diseaseSymptoms: fever, vesicular and ulcerative lesions, edema, ginigivostomatitis, lymphadenopothy, malaiseRecurrence in some people throughout adult lifeKeratoconjunctivitisInadvertent self-transmission (aka, autoinoculation) to eyeCauses lesionsScarring can cause vision impairmentCan lead to an autoimmune response against the eyesGenital herpesSimilar lesions and recurrenceComplications can occurTransmission to newborn infantAseptic meningitisVisceral herpesHerpesvirus Diseases

Herpes simplex viruses (cont.)Clinical conditionsSkin infectionsDocumented in laboratory or health care workers with compromised skinPersons with skin diseases can have serious infectionsEncephalitisHSV-1 is most common cause (proximity to brain)High fatality rate in untreated patients (70%)Survival is often accompanied by permanent neurological disordersNeonatal herpesTransmission: in utero, during birth, after birthHigh fatality rate if untreated (50%)Immunocompromised hostsSystemic infectionsHerpesvirus Diseases

ImmunityImmune response is not sterilizingIgG, IgA, IgMCTL responses are impairedViral proteins block MHC class I pathway47 protein retains class I molecules in the cytoplasmICP47 protein inhibits peptide translocation into the ER lumenCD4+ T cells act as CTL to kill infected cellsCannot engage ganglia cellsHerpesvirus Diseases

Laboratory DiagnosisCytopathologyMultinucleated giant cells from skin scrapingsVirus isolationImmunofluorescenceRestriction digestion of viral DNA (HSV-1 vs. HSV-2)PCRUsed for systemic or encephalitic diseaseSerologyIgG appears in 4-7 daysCannot discriminate HSV-1 from HSV-2Herpesvirus Diseases

EpidemiologyGlobalHSV-1Most commonly acquired by childrenMost adults are seropositiveOnly a small proportion have recrudescence HSV-2Most commonly acquired by young adultsSexually-transmitted diseaseAbout 1 in 6 Americans has HSV-2Fetal/newborn transmissionIncreased risk for HIV infectionHerpesvirus Diseases

Treatment, prevention and controlCheomtherapyAcyclovir drug of choiceNucleoside analogPhosphorylated by HSV thymidine kinaseThen converted into Acy-triphosphate by cellular kinasesIncorporated into newly-synthesized HSV DNA and acts as a chain-terminatorDramatic impact on reduction of transmission and survival of neonatal, visceral and encephalitic HSV infectionsNo vaccine is availableHerpesvirus Diseases

Varicella-Zoster virusVaricella (chickenpox)Zoster (shingles)PathogenesisVaricellaRespiratory transmissionReplication in regional lymphoid tissue (e.g. mediastinal LN)ViremiaInfected mononuclear cells take virus to skin where lesions formVirus sequesters in gangliaImmunity is usually life-longZosterRecurrence of virus in adultsInflammation of ganglia and sensory neuronsHerpesvirus Diseases

Varicella-Zoster virusClinical spectrumAlmost always apparent10-21 day incubationMalaise, fever, rash for about 5 daysComplications are rareOcular infections can lead to impaired visionPrimary infection as an adult is usually more seriousBefore vaccine, about 10 people died each year in the U.S.Immunocompromised patientsZosterUsually occurs in aged or immunodeficient personsOften starts as lesions on the lower backPainfulUsually resolves without complicationsHerpesvirus Diseases

Laboratory diagnosisUsually not necessary except for immunocompromisedVirus isolation in human embryonic cellsSerologyEpidemiologyWorldwideMost children by age 10 (varicella)Occasionally in adults (zoster)TreatmentNo treatment required for healthy persons (except eye infections)Immunocompromised patients can get immune globulin (passive immunization)AcyclovirHerpesvirus Diseases

VaccinationVaccine approved for use in the U.S. in 1995Now recommended for children (MMRV tetravalent)Vaccination resulted in Fewer hospitalizationsSavings of hundreds of millions of dollars in hospital expenses per yearHerpesvirus Diseases

CytomegalovirusLargest genome of the human herpesvirusesIE promoter is driven by cellular transcription factorsPathogenesisUsually asymptomaticCan cause a mononucleosis-like diseaseViremia leads to wide tissue distributionImmunocompromised hosts can have serious pneumoniaCongenital/perinatal infectionsAbout 1% of children in U.S. will be infected with CMV at birthOf these, about 5-10% will have developmental defectsClinical spectrumUsually mild diseaseImmunocompromised can develop systemic diseaseCongenital infections are sometimes fatalHerpesvirus Diseases

ImmunityIgM, IgG, IgAVirus becomes latent with episodes of recurrenceLaboratory diagnosisPCR is method of choiceVirus isolation is slow - two to three weeks before CPESerology is usually not informativeEpidemiologyWorldwideHumans are only known hostTransmission through close contact (oral/respiratory routes)TreatmentGancyclovir for life-threatening infectionsHerpesvirus Diseases

Epstein-Barr virusAround 100 genesTargets B cellsCan also infect epithelial cells of oropharynx, parotid gland, cervixBinds to complement receptor 2 (CR2; aka, CD21)Usually becomes latent in the B cellFewer than 10% of infected cells in vitro release virusCan cause transformationUsed to make immortalized human B cells that secrete monoclonal antibodiesPathogenesisTransmission through salivaInitial replication in epithelial cellsB cells in lymphoid tissuesMost young adults are infectedHerpesvirus Diseases

Clinical spectrumInfectious mononucleosisLengthy incubation period of up to 50 daysSore throat, fever, malaise,Prolonged recoveryOral hairy leukoplakia in HIV patients (epithelial cells)Burkitts lymphomaTumor of jaw area of lymphoid tissuesMost tumors express viral EBNA1Correlates with malaria infectionsChromosomal translocationsHerpesvirus Diseases

Laboratory diagnosisPCRVirus isolation (slow)Serology is not usefulEpidemiologyWorldwidePrevention and controlNo vaccine availableAcyclovir has no effectHerpesvirus Diseases

Other herpesvirusesHHV-6Infects T cellsCauses roseolaOnly a problem in immunocompromised patientsHHV-7Infects T cellsNo known diseaseHHV-8Kaposis sarcoma virusBefore HIV disease, only known to cause disease in men of Mediterranean descent and chemotherapy patientsIsolated from HIV patientsHerpesvirus Diseases

Herpes B virusFormerly known as Herpes simiaeOfficially known as cercopithecine herpesvirus 1Almost always fatal in humansHas high propensity for central nervous system and causes substantial damageSurvivors usually have neurological disordersNo effective treatmentHerpesvirus Diseases