08-cell病毒学virus巴斯德研究所

CelltransformationandoncolysisbyvirusPaulZhouInstitutPasteurofShanghaiOutcomesofviralinfectionofacell•Nonproductiveinfection–noviralreplicationandhostcellsurvivalwithorwithoutviralgenomepersistentasepisomalDNAorintegratedintohostgenome(potentialoncogenesisand/orlatentinfection)•Nonproductiveinfection–noviralreplicationbutnon-survivalofhostcell•Productiveinfectionresultsincelldeath•Productiveinfectionwithoutcelldeath(chronicinfection)Virus-inducedtransformationincellculture•Conversionofmoderncancerresearchintoageneticscience•Oncogenicphenotyperesultsfromdiscretechangesinkeycellularcontrolgenesandfromcorruptionofnormalcellulargrowthsignal•Asingleinfectiousvirusparticleissufficientfortransformation•Allorpartofviralgenomepersistsinthetransformedcells(oftennoproductiveinfectionbutatleastpartofviralgenomeisexpressedCellgrowthregulationpathwaysMechanismsofcelltransformationbyRNAtumorviruses•Cellculture–aquantitativescience•Reversetranscriptionandintegrationbutwithoutcytocidalaction•Theabilitytoacquireandtransducecellulargeneticmaterial(temperaturesensitiveversustransformationdefectivemutants)•Theinsertionalactivationofcellulargenesbytheintegratedprovirus•HTLV-1–theoncogenesisactivityisduetoTaxproteinMechanismofacquisitionofcellularsequencesbyretroviruses-Infectthesamecellwithawildtypevirusandadeletedvirus-Insertionofdeletedretrovirusupstreamofapotentialcellularoncogene-ChimericRNAtranscriptsextendthroughtheoncogene-PackagedchimericRNAandwildtypeRNAintothesamevirion-Duringthenextroundinfection,homologousrecombinationbetweenchimericRNAandwildtypeRNAMycandErbBactivationbyinsertionofavianLeukosisvirusOncogenesismediatedbyessentialretroviralproteinNaturehostsandexperimentalmodelsbyDNAtumorviruses•Inducetumorinitsnaturehost–e.g.HPVandcervicalcarcinomas;EBVandBurkitt’slymphomaandnasopharyngealcarcinomas;andHBVandhepatocellularcarcinomas•Inducetransformationofcellsincultureandformtumorsinexperimentalanimals–e.g.adenovirus,SV40,andPolyomavirusDNAtumortransforminggenesHomologousviralsequencesinvolvedinbindingtotheRbfamilyofproteinsInactivationofRB-mediatedcpntrolofE2FactivityTheE2F1/ARF/Mdm2/p53pathwayMolecularmimicryofE5transmembraneproteinofBPVandgp55proteinofSFFVTargettumorcellsbyoncolyticviruses•Designedtotakeadvantageoffrequenttumor-specificmutationsinantiviraldefensemechanism,e.g.NS1deletedinfluenzavirus,NCVandVSVintumorcellsthatdefectininterferonresponses•Engineeredtobedependentonsignalingpathwaysortranscriptionalprogramsthatareconstitutivelyactivatedintumorcells,e.g.AdenovirusthatislackofE1B-55K(Onyx-015),HSVthatlackofE1B-19K•Torestrictvirusentryintocellsbasedontheexpressionofantigensthatareuniqueorover-expressedontumorcellsurfacee.g.MeaslesvirusinCD46positivetumorcells,CoxsackievirusinCD55positivetumorcells•Toxicpayloads,immune-stimulators,andnaturalpropensityofthevirustopromotetumor-specificinflammationInfectionandkillingoftumorcellsbyanoncolyticvirusBarrierstooptimaldeliveryofoncolyticvirusesinvivo