This edited volume provides insights about the molecular virology, pathoenesis of infection and host responses to varicella-zoster virus, which is a medically important human herpesvirus. The chapters not only discuss genetics and molecular evolution of the virus, but also new structure-based knowledge on the functions of viral glycoproteins. Further, the authors illustrate how mechanisms from the virus are used to take over and remodel host cells during pathogeneis. These mechanisms also enable viral modulation of host cells and evasion of the host immune response. Part of these evasion and survival strategies, is the reaction to triggered host cell responses like autophagy, the stress response, modulation of apoptosis and other cell death pathways. This hands-on knowledge is crucial for students and clinicians in Virology, Immunology, and Infectious Diseases. Chapter "Common features between stroke following varicella in children and stroke following herpes zoster in adults" is available open access under a Creative Commons Attribution 4.0 International License via Springerlink.com.

Varicella-zostervirus(VZV)isamedicallyimportanthumanherpesvirus,belo- ingtothesubfamilyAlphaherpesviridae. Thecapacitytopersistinsensoryneurons isade?ningcharacteristicoftheAlphaherpesviridaesubgroupwhichalsoincludes herpessimplexvirus1and2;likeVZV,simianvaricellavirus(SVV),pseudorabies virus-1(PRV-1),andequineherpesvirus-1(EHV-1)belongtotheVaricellovirus genus. ThebasicelementsoftheinfectiouscycleofVZVinthehumanhostarethat infectionofthena?vehostresultsinvaricella,commonlyknownaschickenpox, latencyisestablishedinsensoryganglia,andreactivationcauseszosteror"sh- gles. "Therelationshipbetweenthecausative agentofvaricellaandzoster was demonstratedmorethan100yearsagowhenchildreninoculatedwithmaterialfrom zosterlesionswereshowntodevelopvaricella. Thelocalizeddistributionofthe zosterrashwasalsorecognizedasdemarcatingthedematomeinnervatedbyaxons fromneuronsineachofthesensoryganglia. Earlyelectronmicroscopystudies showedthatvirusparticleswerepresentinhighconcentrationsinthevesicular ?uidfrombothvaricellaandzosterlesions,andVZVwasamongthe?rstviruses propagatedinvitrobyJohnEndersandThomasWeller. Theintroductionofim- nosuppressivetherapiesformalignancyledtoobservationssuggestingtheneed forcell-mediatedimmunityinthehostresponsetovaricellaanditsroleinma- tainingVZVlatency. Fortunately,earlystudiesofthemolecularvirologyofVZV revealedthatitwasinhibitedbyinterferencewiththethymidinekinasegene,and thelife-threateningandoftenfatalVZVinfectionsexperiencedbythesepatients becametreatablewithantiviraldrugs. Subsequently,thecapacitytogrowVZVin tissueculturewasexploitedtocreatealiveattenuatedVZVvaccinebyMichiaki Tashihaki. Whilenowtakenforgranted,theseearlyinsightsaboutVZVandits characteristicsasahumanpathogenaswellasthedevelopmentofeffectivean- viral drugs and vaccines occurred over many decades. Importantly, these early observationssetthestagefortheremarkableprogressthathasbeenmadeinour understandingofthemolecularbiologyofVZV,thesubtletiesofitstropismfor differentiatedhumancells,includinglymphocytesaswellasskinandneurons,and themechanismsbywhichthevirusachievesanequilibriumwiththehostsothatit persistsnotjustintheindividualbutinthehumanpopulation. v vi Preface Thepurposeofthisvolumeistoreviewkeyareasofprogressinthe?eldofVZV research,aswellasworkontherelatedSVV,writtenbythosewhohavecontributed manyofthenew? ndingsthathaveenrichedourknowledgeoftheuniquech- acteristicsofthisubiquitoushumanpathogen. AlthoughtheVZVgenomeisthe smallestamongthehumanherpesviruses,therapidlyacceleratingpaceofdiscovery about VZV and VZV-host interactions re?ected in these reviews promises to continueasnewtoolsareavailableandnewhypothesesaregeneratedtoexplain howVZVhascreatedandmaintaineditsnicheinthehuman"virome"Therelationshipbetweenthecausative agentofvaricellaandzoster was demonstratedmorethan100yearsagowhenchildreninoculatedwithmaterialfrom zosterlesionswereshowntodevelopvaricella. Thelocalizeddistributionofthe zosterrashwasalsorecognizedasdemarcatingthedematomeinnervatedbyaxons fromneuronsineachofthesensoryganglia. Earlyelectronmicroscopystudies showedthatvirusparticleswerepresentinhighconcentrationsinthevesicular ?uidfrombothvaricellaandzosterlesions,andVZVwasamongthe?rstviruses propagatedinvitrobyJohnEndersandThomasWeller. Theintroductionofim- nosuppressivetherapiesformalignancyledtoobservationssuggestingtheneed forcell-mediatedimmunityinthehostresponsetovaricellaanditsroleinma- tainingVZVlatency. Fortunately,earlystudiesofthemolecularvirologyofVZV revealedthatitwasinhibitedbyinterferencewiththethymidinekinasegene,and thelife-threateningandoftenfatalVZVinfectionsexperiencedbythesepatients becametreatablewithantiviraldrugs. Subsequently,thecapacitytogrowVZVin tissueculturewasexploitedtocreatealiveattenuatedVZVvaccinebyMichiaki Tashihaki. Whilenowtakenforgranted,theseearlyinsightsaboutVZVandits characteristicsasahumanpathogenaswellasthedevelopmentofeffectivean- viral drugs and vaccines occurred over many decades. Importantly, these early observationssetthestagefortheremarkableprogressthathasbeenmadeinour understandingofthemolecularbiologyofVZV,thesubtletiesofitstropismfor differentiatedhumancells,includinglymphocytesaswellasskinandneurons,and themechanismsbywhichthevirusachievesanequilibriumwiththehostsothatit persistsnotjustintheindividualbutinthehumanpopulation. v vi Preface Thepurposeofthisvolumeistoreviewkeyareasofprogressinthe?eldofVZV research,aswellasworkontherelatedSVV,writtenbythosewhohavecontributed manyofthenew?ndingsthathaveenrichedourknowledgeoftheuniquech- acteristicsofthisubiquitoushumanpathogen. AlthoughtheVZVgenomeisthe smallestamongthehumanherpesviruses,therapidlyacceleratingpaceofdiscovery about VZV and VZV-host interactions re?ected in these reviews promises to continueasnewtoolsareavailableandnewhypothesesaregeneratedtoexplain howVZVhascreatedandmaintaineditsnicheinthehuman"virome"sos- cessfully. Further improvements in the clinical management of VZV infection shouldemergeinparallelwithbetterinsightsintoVZVmolecularvirologyand pathogenesis. Stanford,CA,June,2010 AllisonAbendroth AnnM. Arvin JenniferF. Moffat Contents TheVaricella-ZosterVirusGenome ...1 JeffreyI. Cohen VZVMolecularEpidemiology ...15 JudithBreuer RolesofCellularTranscriptionFactorsinVZVReplication ...43 WilliamT. Ruyechan EffectsofVaricella-ZosterVirusonCellCycleRegulatoryPathways ...67 JenniferF. MoffatandRebeccaJ. Greenblatt Varicella-ZosterVirusOpenReadingFrame66ProteinKinase andItsRelationshiptoAlphaherpesvirusUS3Kinases ...79 AngelaErazoandPaulR. Kinchington VZVORF47SerineProteinKinaseandItsViralSubstrates ...99 TeriK. KenyonandCharlesGrose OverviewofVaricella-ZosterVirusGlycoproteinsgC,gHandgL ...113 CharlesGrose,JohnE. Carpenter,WallenJackson,andKarenM. Duus AnalysisoftheFunctionsofGlycoproteinsEandIandTheirPromoters DuringVZVReplicationInVitroandinSkinandT-CellXenografts intheSCIDMouseModelofVZVPathogenesis ...129 AnnM. Arvin,StefanOliver,MikeReichelt,JenniferF. Moffat, MarvinSommer,LeighZerboni,andBarbaraBerarducci Varicella-ZosterVirusGlycoproteinM ...147 YasukoMoriandTomohikoSadaoka vii viii Contents VaricellaZosterVirusImmuneEvasionStrategies ...155 AllisonAbendroth,PaulR. Kinchington,andBarrySlobedman VZVInfectionofKeratinocytes:ProductionofCell-FreeInfectious VirionsInVivo ...173 MichaelD. GershonandAnneA. Gershon Varicella-ZosterVirusTCellTropismandthePathogenesis ofSkinInfection ...189 AnnM. Arvin,JenniferF. Moffat,MarvinSommer,StefanOliver, XibingChe,SusanVleck,LeighZerboni,andChia-ChiKu ExperimentalModelstoStudyVaricella-ZosterVirusInfection ofNeurons ...211 MeganSteain,BarrySlobedman,andAllisonAbendroth MolecularCharacterizationofVaricellaZosterVirusinLatently InfectedHumanGanglia:PhysicalStateandAbundanceofVZV DNA,QuantitationofViralTranscriptsandDetection ofVZV-Speci?cProteins ...229 YevgeniyAzarkh,DonGilden,andRandallJ. Cohrs NeurologicalDiseaseProducedbyVaricellaZosterVirusReactivation WithoutRash ...2 43 DonGilden,RandallJ. Cohrs,RaviMahalingam,andMariaA. Nagel Varicella-ZosterVirusNeurotropisminSCIDMouse-Human DorsalRootGangliaXenografts ...255 L. Zerboni,M. Reichelt,andA. Arvin RodentModelsofVaricella-ZosterVirusNeurotropism ...277 JeffreyI. Cohen SimianVaricellaVirus:MolecularVirology ...291 WayneL. Gray SimianVaricellaVirusPathogenesis ...309 RaviMahalingam,IlhemMessaoudi,andDonGilden Varicella-ZosterVirusVaccine:MolecularGenetics ...323 D. ScottSchmid VZVTCell-MediatedImmunity ...341 AdrianaWeinbergandMyronJ. Levin Contents ix PerspectivesonVaccinesAgainstVaricella-ZosterVirusInfections ...359 AnneA. GershonandMichaelD. Gershon Index ...373 . Contributors Allison Abendroth Department of Infectious Diseases and Immunology, UniversityofSydney,BlackburnBuilding,Room601,Camperdown,NSW 2006, Australia and Centre for Virus Research, Westmead Millennium Institute,Westmead,NSW2145,Australia,allison. abendroth@sydney. edu. au AnnM. Arvin StanfordUniversitySchoolofMedicine,G311,Stanford,CA 94305,USA,aarvin@stanford.

Varicella-zostervirus(VZV)isamedicallyimportanthumanherpesvirus,belo- ingtothesubfamilyAlphaherpesviridae. Thecapacitytopersistinsensoryneurons isade?ningcharacteristicoftheAlphaherpesviridaesubgroupwhichalsoincludes herpessimplexvirus1and2;likeVZV,simianvaricellavirus(SVV),pseudorabies virus-1(PRV-1),andequineherpesvirus-1(EHV-1)belongtotheVaricellovirus genus. ThebasicelementsoftheinfectiouscycleofVZVinthehumanhostarethat infectionofthena?vehostresultsinvaricella,commonlyknownaschickenpox, latencyisestablishedinsensoryganglia,andreactivationcauseszosteror"sh- gles. "Therelationshipbetweenthecausative agentofvaricellaandzoster was demonstratedmorethan100yearsagowhenchildreninoculatedwithmaterialfrom zosterlesionswereshowntodevelopvaricella. Thelocalizeddistributionofthe zosterrashwasalsorecognizedasdemarcatingthedematomeinnervatedbyaxons fromneuronsineachofthesensoryganglia. Earlyelectronmicroscopystudies showedthatvirusparticleswerepresentinhighconcentrationsinthevesicular ?uidfrombothvaricellaandzosterlesions,andVZVwasamongthe?rstviruses propagatedinvitrobyJohnEndersandThomasWeller. Theintroductionofim- nosuppressivetherapiesformalignancyledtoobservationssuggestingtheneed forcell-mediatedimmunityinthehostresponsetovaricellaanditsroleinma- tainingVZVlatency. Fortunately,earlystudiesofthemolecularvirologyofVZV revealedthatitwasinhibitedbyinterferencewiththethymidinekinasegene,and thelife-threateningandoftenfatalVZVinfectionsexperiencedbythesepatients becametreatablewithantiviraldrugs. Subsequently,thecapacitytogrowVZVin tissueculturewasexploitedtocreatealiveattenuatedVZVvaccinebyMichiaki Tashihaki. Whilenowtakenforgranted,theseearlyinsightsaboutVZVandits characteristicsasahumanpathogenaswellasthedevelopmentofeffectivean- viral drugs and vaccines occurred over many decades. Importantly, these early observationssetthestagefortheremarkableprogressthathasbeenmadeinour understandingofthemolecularbiologyofVZV,thesubtletiesofitstropismfor differentiatedhumancells,includinglymphocytesaswellasskinandneurons,and themechanismsbywhichthevirusachievesanequilibriumwiththehostsothatit persistsnotjustintheindividualbutinthehumanpopulation. v vi Preface Thepurposeofthisvolumeistoreviewkeyareasofprogressinthe?eldofVZV research,aswellasworkontherelatedSVV,writtenbythosewhohavecontributed manyofthenew? ndingsthathaveenrichedourknowledgeoftheuniquech- acteristicsofthisubiquitoushumanpathogen. AlthoughtheVZVgenomeisthe smallestamongthehumanherpesviruses,therapidlyacceleratingpaceofdiscovery about VZV and VZV-host interactions re?ected in these reviews promises to continueasnewtoolsareavailableandnewhypothesesaregeneratedtoexplain howVZVhascreatedandmaintaineditsnicheinthehuman"virome"Therelationshipbetweenthecausative agentofvaricellaandzoster was demonstratedmorethan100yearsagowhenchildreninoculatedwithmaterialfrom zosterlesionswereshowntodevelopvaricella. Thelocalizeddistributionofthe zosterrashwasalsorecognizedasdemarcatingthedematomeinnervatedbyaxons fromneuronsineachofthesensoryganglia. Earlyelectronmicroscopystudies showedthatvirusparticleswerepresentinhighconcentrationsinthevesicular ?uidfrombothvaricellaandzosterlesions,andVZVwasamongthe?rstviruses propagatedinvitrobyJohnEndersandThomasWeller. Theintroductionofim- nosuppressivetherapiesformalignancyledtoobservationssuggestingtheneed forcell-mediatedimmunityinthehostresponsetovaricellaanditsroleinma- tainingVZVlatency. Fortunately,earlystudiesofthemolecularvirologyofVZV revealedthatitwasinhibitedbyinterferencewiththethymidinekinasegene,and thelife-threateningandoftenfatalVZVinfectionsexperiencedbythesepatients becametreatablewithantiviraldrugs. Subsequently,thecapacitytogrowVZVin tissueculturewasexploitedtocreatealiveattenuatedVZVvaccinebyMichiaki Tashihaki. Whilenowtakenforgranted,theseearlyinsightsaboutVZVandits characteristicsasahumanpathogenaswellasthedevelopmentofeffectivean- viral drugs and vaccines occurred over many decades. Importantly, these early observationssetthestagefortheremarkableprogressthathasbeenmadeinour understandingofthemolecularbiologyofVZV,thesubtletiesofitstropismfor differentiatedhumancells,includinglymphocytesaswellasskinandneurons,and themechanismsbywhichthevirusachievesanequilibriumwiththehostsothatit persistsnotjustintheindividualbutinthehumanpopulation. v vi Preface Thepurposeofthisvolumeistoreviewkeyareasofprogressinthe?eldofVZV research,aswellasworkontherelatedSVV,writtenbythosewhohavecontributed manyofthenew?ndingsthathaveenrichedourknowledgeoftheuniquech- acteristicsofthisubiquitoushumanpathogen. AlthoughtheVZVgenomeisthe smallestamongthehumanherpesviruses,therapidlyacceleratingpaceofdiscovery about VZV and VZV-host interactions re?ected in these reviews promises to continueasnewtoolsareavailableandnewhypothesesaregeneratedtoexplain howVZVhascreatedandmaintaineditsnicheinthehuman"virome"sos- cessfully. Further improvements in the clinical management of VZV infection shouldemergeinparallelwithbetterinsightsintoVZVmolecularvirologyand pathogenesis. Stanford,CA,June,2010 AllisonAbendroth AnnM. Arvin JenniferF. Moffat Contents TheVaricella-ZosterVirusGenome ...1 JeffreyI. Cohen VZVMolecularEpidemiology ...15 JudithBreuer RolesofCellularTranscriptionFactorsinVZVReplication ...43 WilliamT. Ruyechan EffectsofVaricella-ZosterVirusonCellCycleRegulatoryPathways ...67 JenniferF. MoffatandRebeccaJ. Greenblatt Varicella-ZosterVirusOpenReadingFrame66ProteinKinase andItsRelationshiptoAlphaherpesvirusUS3Kinases ...79 AngelaErazoandPaulR. Kinchington VZVORF47SerineProteinKinaseandItsViralSubstrates ...99 TeriK. KenyonandCharlesGrose OverviewofVaricella-ZosterVirusGlycoproteinsgC,gHandgL ...113 CharlesGrose,JohnE. Carpenter,WallenJackson,andKarenM. Duus AnalysisoftheFunctionsofGlycoproteinsEandIandTheirPromoters DuringVZVReplicationInVitroandinSkinandT-CellXenografts intheSCIDMouseModelofVZVPathogenesis ...129 AnnM. Arvin,StefanOliver,MikeReichelt,JenniferF. Moffat, MarvinSommer,LeighZerboni,andBarbaraBerarducci Varicella-ZosterVirusGlycoproteinM ...147 YasukoMoriandTomohikoSadaoka vii viii Contents VaricellaZosterVirusImmuneEvasionStrategies ...155 AllisonAbendroth,PaulR. Kinchington,andBarrySlobedman VZVInfectionofKeratinocytes:ProductionofCell-FreeInfectious VirionsInVivo ...173 MichaelD. GershonandAnneA. Gershon Varicella-ZosterVirusTCellTropismandthePathogenesis ofSkinInfection ...189 AnnM. Arvin,JenniferF. Moffat,MarvinSommer,StefanOliver, XibingChe,SusanVleck,LeighZerboni,andChia-ChiKu ExperimentalModelstoStudyVaricella-ZosterVirusInfection ofNeurons ...211 MeganSteain,BarrySlobedman,andAllisonAbendroth MolecularCharacterizationofVaricellaZosterVirusinLatently InfectedHumanGanglia:PhysicalStateandAbundanceofVZV DNA,QuantitationofViralTranscriptsandDetection ofVZV-Speci?cProteins ...229 YevgeniyAzarkh,DonGilden,andRandallJ. Cohrs NeurologicalDiseaseProducedbyVaricellaZosterVirusReactivation WithoutRash ...2 43 DonGilden,RandallJ. Cohrs,RaviMahalingam,andMariaA. Nagel Varicella-ZosterVirusNeurotropisminSCIDMouse-Human DorsalRootGangliaXenografts ...255 L. Zerboni,M. Reichelt,andA. Arvin RodentModelsofVaricella-ZosterVirusNeurotropism ...277 JeffreyI. Cohen SimianVaricellaVirus:MolecularVirology ...291 WayneL. Gray SimianVaricellaVirusPathogenesis ...309 RaviMahalingam,IlhemMessaoudi,andDonGilden Varicella-ZosterVirusVaccine:MolecularGenetics ...323 D. ScottSchmid VZVTCell-MediatedImmunity ...341 AdrianaWeinbergandMyronJ. Levin Contents ix PerspectivesonVaccinesAgainstVaricella-ZosterVirusInfections ...359 AnneA. GershonandMichaelD. Gershon Index ...373 . Contributors Allison Abendroth Department of Infectious Diseases and Immunology, UniversityofSydney,BlackburnBuilding,Room601,Camperdown,NSW 2006, Australia and Centre for Virus Research, Westmead Millennium Institute,Westmead,NSW2145,Australia,allison. abendroth@sydney. edu. au AnnM. Arvin StanfordUniversitySchoolofMedicine,G311,Stanford,CA 94305,USA,aarvin@stanford.