2000 J Viral Hepatitis- How can the cellular immune response control hepatitis B virus replication

JournalofViralHepatitis,2000,7,321±326

REVIEW

HowcanthecellularimmuneresponsecontrolhepatitisBvirusreplication?

M.K.Maini1,2andA.Bertoletti1

ofLondonMedicalSchool,London,UK

1

InstituteofHepatologyand2DepartmentofSexuallyTransmittedDiseases,UniversityCollege

SUMMARY.Inthisreviewwefocusonaspectsofthevirus-

speci®ccellularimmuneresponse,althoughweshouldpointoutthatallthecomponentsoftheinnateandadaptiveimmuneresponsearelikelytoplayaroleinsuccessfulcontrolofhepatitisBvirus(HBV)infection.Weconcentrateparticularlyontherelevanceofthepolyclonalityandmul-tispeci®cityoftheHBV-speci®ccytotoxicTcellresponsetoitsantiviralactivity.Inthiscontext,wediscussthepossiblerole

ofviralescapemutationsandhighlightevidencefromothermodelsofthebene®tofmultispeci®cityinantiviralresponses.WestressthecontributionofCD4helpforeffec-tiveCD8responsesandraisethepossibilitythatHBVmayproducefactorsinhibitingtheantiviralresponse.

Keywords:multispeci®city,HBV,CTL,viralcontrol.

INTRODUCTION

HowcanwegaininsightintowhichimmuneresponsesaremostimportantforthesuccessfulcontrolofhepatitisBvirus(HBV)replication?Primarily,wehavereliedonthestudyofhumanimmuneresponsesassociatedwithHBVcontrol,namelythoseseenfollowingacutesymptomaticHBVinfec-tionandinspontaneousortherapy-inducedcasesofsero-conversion±hepatitisBeantigen(HBeAg)toHBeantibody(HBeAb)±followingchronicinfection.Duringtheseappar-entlydifferentmanifestationsofHBVinfectionthepatientssharetheabilitytosubstantiallyandrapidlydecreasetheirviralload.

Inthiscontext,itisimportanttostressthateffectivecontrolofviralreplicationdoesnotnecessarilyimplyviraleradication.ItisnowwidelyacceptedthatpatientswhorecovercompletelyfollowingacutehepatitisdonoteradicateHBVinfection.ReportshaveshownthatHBVispresentandretainstheabilitytoreplicateintheliverofpatientswhohaveclearedserumhepatitisBsurfaceantigen(HBsAg)[1±4].Suchpersistenceoflow-levelHBVreplicationmayinfactbecriticaltomaintainanef®cientHBV-speci®cTcellresponse,andvirusreactivationhasonlybeendocumentedinthesettingofchemotherapyorotherstatesofimmuno-suppression[5,6],withtheresultantimpairmentofTcellimmuneresponses[5,6].

Abbreviations:CTL,cytotoxicT-lymphocyte;HBeAg,hepatitisBeantigen;HBV,hepatitisBvirus;TCR,T-cellreceptor.

Correspondence:AntonioBertoletti,InstituteofHepatology,Uni-versityCollegeofLondonMedicalSchool,69±75CheniesMews,LondonWC1E6HX.

Inthisreviewweconcentrateonstudiesthathavedis-sectedtheimmunologicaleventstakingplaceinpatientswithsuccessfulinhibitionofviralreplication,toseewhetherourexistingknowledgecanshedlightonthefailureoftheimmunesystemtocontrolHBVinfection.

ISAMULTISPECIFICCD8RESPONSETHEKEYFACTORFORCONTROLOFHBVREPLICATION?

AnalysisofHBV-speci®ccytotoxicT-lymphocyte(CTL)responsesinacuteinfectionhaverepeatedlydemonstratedthateffectiveviralcontrolisassociatedwithCTLsspeci®cforanumberofdifferentepitopeswithinHBVcore,poly-meraseandenvelopeproteins[4,7±10].Themagnitudeoftheseresponseshasrecentlybeenrevealedbythemoresensitivedetectionmethodofhumanleucocyteantigen(HLA)-A2/HBV-epitopespeci®ctetramers,visualizingCD8cellsspeci®cforepitopeswithincore,polymeraseanden-velope[11].DirectanalysisofthefrequencyofCD8cellsinacutelyinfectedpatients,whosuccessfullycontrolHBVinfection,demonstratesaquantitativehierarchyofCD8cellsspeci®cforcore,polymeraseandenvelope.Core18±27-speci®cCD8cellsarethemostnumerous,accountingforupto1.3%ofcirculatingCD8cells,butarealwaysaccompaniedbyaCD8responsedirectedagainsttheotherepitopes.Furthermore,precise,directquanti®cationofHBV-speci®cCD8cellsinthecirculationofpatientswhocontrolHBVinfectionrevealsthatthenumberofcirculatingcore18±27-speci®cCD8cellsishigherinacuteHBVinfection(withfrequenciesthatpersistat»100core18±27-speci®cCD8ml)1ofperipheralblood,atleast1yearaftertherecoveryofinfection),comparedwithHBeAg-positive

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322M.K.Maini&A.Bertoletti

cellstorecognizeandexpandinresponsetothecore18±27epitopewithsingle,conservativeaminoacidsubstitutions,wefoundasurprisinglackoffunctionalplasticity(M.K.Maini,submitted).InthiscasethereforepolyclonalityoftherespondingCD8cellsdidnotallowfor¯exiblerec-ognitionofpotentialmutationswithintheviralepitope,suggestingthatpolyclonalityofasingleandstrongCTLresponsemaynotpreventviralescape.Thusitseemsthatmultispeci®city,inotherwordstheabilitytomountCTLresponsesagainstdifferentepitopes,istheonlyfeatureconsistentlycontributingtoasuccessfulHBV-speci®cCTLresponse.InadditiontotherepeateddemonstrationofthepresenceofCTLmultispeci®cityinpatientswhosuccessfullycontrolHBV[4,7,9,15]studiesinotherviralsystemshaverecentlyhighlightedthecontributionofmultispeci®citytoviralcontrol[16].

HeterozygosityateachofthethreehumanMHCclassI(HLA)allelesshouldmaximizethenumberofdifferentepitopesthatcanbepresentedsimultaneouslyandthere-forerepresentsanindirectmeasurementofmultispeci®city.Thebiologicaladvantageofheterozygosityintermsofcontrolofahighlyvariablevirushasrecentlybeencon-®rmedbythedemonstrationofapowerfulassociationwithhumanimmunode®ciencyvirus(HIV)progressionrates[17].HLAclassItypinginalargecohortofHIV-1-infectedindividualsrevealedsigni®cantlyfasterratesofprogressioninpatientswithhomozygosityatoneormorealleles.Inadditiontotheabsolutenumberofdifferentalleles,partic-ularallelesorcombinationsofallelesmayalsobeassoci-atedwithbetterviralcontrolbecauseoftheircapacitytopresentagreaternumberofepitopesforthatparticularvirus[18];thismayexplaintheassociationofHLA-A2withhumanT-lymphotrophicvirus-1(HTLV-1)control

[19].

chronicHBVpatients,inwhomsuchcellsarebarelydetect-ableinthecirculation.TheseresultsareinlinewithpreviousstudiesshowingaveryweakCTLresponseinpa-tientswithchronicHBVinfection,usuallyonlydetectableduringspontaneousortherapy-inducedclearanceofHBeAg[12],andsupportthetheorythatastrongandmulti-speci®cCTLresponseislinkedtotheabilitytocontrolHBVinfection[13].

Fromthesedataithasbeensuggestedthatpolyclonalityandmultispeci®cityarekeyfactorsforHBVcontrol.Beforediscussingthishypothesisweshould®rstclarifyhowthemultispeci®cityandpolyclonalityoftheCTLresponsediffer.ThenumberofdifferentepitopesrecognizedbyaCTLre-sponserepresentsitsmultispeci®city,whereasthenumberofdifferentT-cellreceptors(TCRs)abletointeractwithagivenmajorhistocompatibilitycomplex(MHC)/peptidecomplexrepresentsthepolyclonalityofaCTLresponse(Fig.1).Bothfeaturesmayplayanimportantroleinthegenerationofa¯exibleCTLresponseabletorespondtoarapidlymutatingvirus.

ThepresenceofpolyclonalcytotoxicTcellsabletorecognizeasingleepitopemayaffordapracticaladvan-tagebecausestructurallydifferentTCRsmightallowim-mediaterecognitionofepitopeswithsubstitutedresidues[14]andthusactpromptlyagainstarapidlymutatingvirus.WehaverecentlyaddressedthisquestioninthecontextoftheCD8responsetothecore18±27epitope,usingHLA/peptidetetramerstoidentifythevirus-speci®cTcellsdirectlyexvivofromagroupofHLA-A2patientswithacuteHBVinfection.Co-stainingoftheCD8cellsspeci®cforthisepitopewithmonoclonalantibodiesspeci®cforthedifferentVbchainsoftheTCRrevealedconsiderableheterogeneityofTCRusageofcore18±27-speci®cCD8cells.However,whenwetestedtheabilityofthesepolyclonalHBV-speci®cCD8

Fig.1SchematicrepresentationofapolyclonalcytotoxicT-lymphocyte(CTL)responseagainstasingleepitopecomparedwithamultispeci®cCTLresponse.HLA,humanleucocyteantigen.

Ó2000BlackwellScienceLtd,JournalofViralHepatitis,7,321±326

Furthersupportfortheimportanceofmultispeci®cityinsuccessfulviralcontrolcomesfromthestudyofsixchim-panzeesduringacuteHCVhepatitis[20].Thetwochim-panzeesthatresolvedinfectionhadstrongCTLresponsessynchronouslytargetingatleastsixviralregions,withrecog-nitionofnineepitopesrestrictedthroughallsixMHCclassIallotypesinonecase.Thesemultispeci®cCTLresponseswerepresentfromtheveryearlyphaseofinfection,whichmaybecriticalindeterminingtheoutcome.

VIRALMUTATIONSINTHEABSENCEOFCTLMULTISPECIFICITY

TheimportanceofCTLmultispeci®cityintheabilitytocontrolHBVreplicationhasbeenaddressedbydemonstrat-ingthepresenceofviralescapewhensucharesponseislacking[21].AlthoughthepresenceofvirusescontainingcodingmutationshasbeenreportedincasesofHBVinfec-tion[22±25],theircontributiontoescapefromCTLcontrolremainstobede®ned[26].However,whenafunctionallymonospeci®cCTLresponsewasdemonstratedinchronicHBVpatients,HBVmutantsabletoescapeCTLrecognitionwerefound[21].Inthisstudy,twopatientswithchronicHBVinfectionshowedastrongHLA-A2-restrictedCTLresponseagainstthecoreregion18±27,butfailedtoexpressaCTLresponsetoanyoftheotherHLA-A2-restrictedCTLepitopesinHBVthataregenerallyimmunogenicinacutelyinfectedpatients(Fig.2).Sequencingtheinfectingvirusindicatedthatthesetwopatientswereinfectedwithaho-mogeneouspopulationofHBVcarryingmutationsinthecore18±27epitopethatcouldreducebindingtotheHLA-A2moleculeandTcellrecognitionoftheepitopebywild-typecore18±27-speci®cCTLclones.Furthermore,thevariantviruseswerenotrecognizedatallbytheCTLresponsepre-sentinthetwopatients,whichonlyrecognizedthewild-typesequence,demonstratingthatthevariantpeptidewasunabletoinduceaCTLresponse.Theoretically,theimmunesystemcouldattempttomountanewresponsespeci®cforthemutatedepitope,butrecentdatainlymphochoriomen-ingitisvirus(LCMV)infectionhavedemonstratedthatonceaCTLresponseagainstanepitopehasbeen®xed,theimmunesystemmayfailtodevelopanewCTLresponseagainstthemutatedepitope[27].

Theseresults,showingthataCTLresponseagainstasingleepitopeisnotsuf®cienttocontrolthereplicationofthevirus,highlightagaintheimportanceofamultispeci®cCTLresponseincontrollingthevirus.

FACTORSIMPORTANTFORTHEINDUCTIONOFAMULTISPECIFICCTLRESPONSE

Themultispeci®cCD8responseistheend-stageeffectormechanism,whichcanacttoeliminateHBV-infectedtargetcellsbycytolyticornon-cytolyticpathwaysofclearance[28].However,thegenerationandmaintenanceofthese

effectorcellsrequireef®cientantigenpresentationandCD4help[29,30].Accumulatingevidencesuggeststhatastrongvirus-speci®cCD4+TcellresponsewithapredominantlyThelper1(Th1)phenotypeisoneimportantcomponentfortheeffectivemaintenanceofCTLresponses[30,31].Effectiveantigenpresentationintheappropriatecytokineenviron-mentisrequiredtogenerateTh1-polarizedCD4cells,andinterleukin-12(IL-12)hasbeenproposedtobeakeycyto-kineinthiscontext[32].EvidencethatIL-12isrelevanttothecontrolofHBVinfectioncomesfromtwostudies.IL-12hasbeenshowntobecapableofshiftingaThelper2(Th2)-biasedphenotypetoaTh1predominanceinHBeAgtrans-genicmice[33].LevelsofIL-12havealsobeenshowntoincreaseininterferon(IFN)-inducedHBeseroconversionofchronicHBV-infectedpatients[34].ThisIL-12increasewasconcomitantwithanincreaseofIFN-candvirus-speci®cCD4proliferativeresponses,suggestinganenhancementofTh1

activity.

324M.K.Maini&A.Bertoletti

TheimportanceofCD4inpromotingCTLsurvivalandeffectorfunction(ultimatelyleadingtoHBVcontrol)issup-portedbythefactthatCD4responsesareonlyconsistentlydetectableinacuteinfection[35,36]andinchronicpatientsundergoingHBeAgseroconversion[37±39].InacutelyinfectedHBVpatientswithsuccessfulvirus-speci®cCD8responses,notonlyareCD4responsesstrong[35,36]andTh1-like[40],butalsomultispeci®c,withresponsesseentoanumberofdifferentepitopeswithinthestructuralproteinsinvestigatedtodate[41].Thismultispeci®cityoftheCD4responsemaybehighlyrelevanttoviralcontrolas,inapopulation-basedgeneticstudy,heterozygosityofclassIIalleleshasbeenshowntobeassociatedwithmorefavour-ableHBVcontrol[42].

Fromthedatapresented,itisclearthatpatientswhoareabletocontrolHBVviralreplicationareabletoexpressaco-ordinateTcellimmuneresponsecharacterizedbytheexpansionofafunctionallymultispeci®cCTLresponse.However,wedonothaveaclearanswerastowhychronicHBVpatients,withahighHBVreplicationrate,arenotabletomountacomparablelevelofHBV-speci®cTcellimmuneresponses.Geneticfactors[42,43]andverticalHBVtrans-mission[44]playarole,butevidencesuggeststhatthevirusitselfmayalterTcellfunction.

TheproductionofHBeAg,asecreted,non-particulateformofnucleoprotein,hasbeendemonstratedtomediateimmunoregulatoryfunction[45].Inamurinemodelsystem,Milichetal.foundthatHBeAgcancrosstheplacentaandestablishThcelltolerance[46].Morerecently,theyshowedthatHBeAgdeletesHBeAg-speci®cTh1cellsandactuallyskewstheHBV-speci®cTcellresponsetowardsTh2,becauseHBeAg-speci®cTh2cellsmayspeci®callyavoidtoleranceinductionbyFas-mediatedperipheraldeletion[47].ThushighlevelsofHBeAgproductioncouldberesponsiblefordeviatingtheHBe/core-speci®cCD4responseinaTh2direction,therebyhelpingtomaintainviralpersistence.However,amoregeneralizedsuppressionofCD4prolif-erativeresponsestorecallantigensandmitogenshasalsobeenobservedinpatientswithchronicHBVinfection[47,48].Thisraisesthepossibilityofproductionofa`sup-pressivefactor',supportedbytherecentdataonreconsti-tutionofCD4responsesfollowinglamivudinetherapy[47].Inthiswork,recoveryofbothvirus-speci®candnon-speci®c(mitogenandrecallantigeninduced)responseswasobservedrapidlyfollowingHBVDNAdecline,whereastherelationshipbetweenreductioninHBeAgconcentrationandrecoveryoftheTcellresponsewasnotclear.ThesedatasuggestthatHBVreplicationcouldleadtoproductionofHBV-encodedfactors(amongwhichHBeAgwouldbeacandidate)thatdirectlyinterferewithTcellimmuneresponses,asdescribedforothervirusesthatproducefactorscapableofblockingtheproductionoractivityofcertaincytokines[49].ThemechanismbywhichHBVcouldmedi-ateCD4hyporesponsivenessremainselusive,butcouldpotentiallyshedlightonthecausesofitschronicity.

CONCLUDINGREMARKS

Inthisreview,wefocusonthefeaturesoftheTcellimmuneresponseinHBV-infectedpatientsthatsuccessfullycontrolviralreplication.Allthesestudiesstresstheimportanceofamultispeci®cCD8andTh1responseinthecontrolofHBVinfection.However,anumberoflimitationshavesofarhamperedacompleteunderstandingofthecharacteristicsofsuccessfulHBV-speci®cimmuneresponses.Iftheselimita-tionscouldbeovercome,wewouldbeinabetterpositiontounderstandwhichcomponentsoftheresponsearefailingincasesofchronicity.

Forexample,informationinregardtotheThCD4responsehasbeenlimitedtotheresponsesagainstHBVstructuralproteins,withlittleinformation[50]regardingtheimportanceoftheCD4responseagainstnon-structuralproteins(Xandpolymerase).Moreover,intheabsenceofanef®cientmodelinwhichhumancellscanbeinfectedwithHBVinvitro,thestudyoftheCD8Tcellresponsehasbeenmostlyperformedoncirculatinglymphocytesusingpeptidestoexpandtheirnumberinvitrobeforefunctionalanalysis[7,9,12,15,51±53].Thisexperimentalapproachcannotmimictheprocessingofendogenouslysynthesizedviralantigensandithasnotthereforebeenpossibletodetermineimmunodominancebetweendifferentepitopes.Inaddition,onlyHLA-A2-restrictedCTLresponseshavebeenstudiedindetail,andinformationaboutotherCTLepitopesrestrictedbydifferentallelesisscarce[7,54].

Moreimportantly,allthesestudiesrequireelaborateandlengthyTcellstimulationinvitro,whichmaybiasresultstowardsthosecellsabletosurvivethecultureconditions.Tetramerstudieshavealreadyshownhowthequanti®cationofHBV-speci®cCTLcandifferwhenthefrequencyofCTLiscalculateddirectlyorafterantigenstimulation[11].ItisthusincreasinglyimportantthatweanalysethepresenceandfunctionalfeaturesofHBV-speci®cTcellsdirectly,avoidingrepetitiveinvitrostimulation.Newtechnologicaladvances,suchasHLAclassIpeptidetetramericcomplexesandanti-gen-speci®cintracellularcytokinestaining,havegivenusthetoolstodirectlyanalysethefeaturesoftheimmuneresponseduringHBVinfection,allowinganin-depthunderstandingofHBVimmunopathogenesis.

ACKNOWLEDGEMENTS

WewouldliketothankallourcolleaguesattheInstituteofHepatology,UCL,LondonandLaboratorioImmunopatologiaVirale,OspedalediParma,Parma,whocontributedtotheworkdiscussedhere.WearealsogratefultoNicolaiNaoumovandRichardGilsonfortheirusefulcommentsonthisreview.

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