Download FOR IMMEDIATE RELEASE Opening the immune system`s “black box”

FORIMMEDIATERELEASE
Openingtheimmunesystem’s“blackbox”
LJIresearchersfirsttodirectlytrackhowthelatestHIVvaccinecandidateelicitsasuccessful
antibodyresponse,revealingcrucialimmunologicalfeaturesandbarriers
November28,2016
LAJOLLA,CA—IntheglobalquesttogettheongoingAIDSepidemicundercontrol,dozensof
HIVvaccinecandidateshavebeentestedinclinicaltrialsbutasafeandeffectiveHIVvaccine
hasyettoemerge.Untilnow,researcherstryingtounderstandwhysomanyattemptshave
failed,hadbeenlimitedtomeasuringantibodytitersinperipheralbloodweeksormonthsafter
immunizationwithavaccinecandidate,whilegerminalcenters,thecentralhubforthe
generationandfine-tuningofhigh-affinityantibodies,hadremainedsomethingofa“black
box.”
Now,fortheveryfirsttime,researchersatLaJollaInstituteforAllergyandImmunologywere
abletodirectlyprobegerminalcentersandshedlightontheimmunologicalprocessesbywhich
avaccineelicitsaprotectiveimmuneresponse.Theirfindings,publishedinthecurrentissueof
CellReports,revealedimportantimmunologicalfeaturesandbottlenecksthatdetermine
whetherimmunizationissuccessfulandprovideavaluabletooltotrackthepotentialofnovel
HIVvaccinecandidatesinupcominghumanphaseIclinicaltrials.
“Whenyoucan’tmeasurewhat’sgoingoningerminalcenterstofindoutwhatwentwrong,
youdon’tknowhowtobestmoveforward,”saysthestudy’sleadauthorShaneCrotty,Ph.D.,a
professorintheInstitute’sDivisionofVaccineDiscovery.“Thishasbeenalongstanding
probleminimmunologyandthefailuretodevelopaHIVvaccinehashighlightedtheproblem
becauseithasprovenparticularlydifficulttogenerateprotectiveimmunityagainstthevirus.”
MorethantwomillionpeopleareinfectedwithHIVeveryyear.Althoughavailabletreatment
optionscaneffectivelystallthevirus,onlyroughlyhalfofHIV-infectedindividualshaveaccess
toantiviraldrugs.VaccinesarethemosteffectivemeanstopreventHIVinfectionsanda
preventiveHIVvaccinewouldhaveatremendousimpactonglobalhealth.Foranyvaccineto
besuccessful,ithastoinducebroadly“neutralizing”antibodies(nAbs),whichrenderan
invadingpathogenharmlessbeforeitgetsachangetoinfectitshost.
BeforeBcellscanstartproducingnAbstheyhavetoteamupwithso-calledfollicularhelperT
cells(TFHcells)ingerminalcenters,whicharelocatedinperipherallymphnodes.ThereBcells
undergoatightlyorchestrated,multi-stepeducationandmaturationprocess,whichselectively
promotestheproliferationofBcellsthatproducehigh-affinityantibodiesandweedsoutthose
thatproducelesspotentones.Ithasbeenspeculatedthatgerminalcentersareveryimportant
forHIVneutralizingantibodyresponses.
TryingtofindawaytodirectlytrackthecharacteristicsofasuccessfulnAbresponsewithin
germinalcenters,ColinHavenar-Daughton,Ph.D.,thestudy’sfirstauthor,wonderedwhether
lymphnodefineneedleaspirates(LNFNAs),whichhavelongbeusedbyoncologiststodetect
thepresenceofmetastases,couldprovidecriticalinformation.
HeteamedupwithexpertsattheYerkesNationalPrimateResearchCentertofollowacohort
of12rhesusmonkeysthathadbeenimmunizedwithanovelHIVenvelopeproteintrimer
knownasSOSIP.v5.2,whichcloselymimicsthevirus’surface.Thatproteinwasdevelopedby
collaboratorsatCornellandtheUniversityofAmsterdam.“Theseenvelopeproteinshavejust
recentlybecomeavailableforimmunizationsandmostlikelywillgointophaseIhumantrials
soon,”explainHavenar-Daughton.
InthecurrentstudytheSOSIPproteinelicitedneutralizingantibodiesin9outof12subjects,
whichisthebestHIVneutralizingantibodyresponsereportedtodateforacandidateHIV
vaccineprotein.“Itwasaverygoodresponsebutifyougointohumansyouwanteverybody
makingneutralizingantibodiesandnotjustsomepeople,”hesays.“Weneedtosolvethis
problem.”
Havenar-Daughtonthinkshemayhavefoundaway.“WecouldconfirmthatLNFNAsprovidea
valuableandinformativewindowintogerminalcenterstoexplorethedifferencebetween
immuneresponsesthatresultinHIVneutralizingantibodiesandthosethatdidn’t,”hesays.
AddsGuidoSilvestri,M.D.,ChiefoftheDivisionofMicrobiology&ImmunologyattheYerkes
NationalPrimateResearchCenter,whoseteamperformedtheLNFNAs:"Weareveryexcited
aboutthevalidationofaveryinformativeyetnon-invasivesamplingtechnologysuchasthefine
needleaspirationoflymphnodesforpre-clinicalstudiesofnovelcandidateAIDSvaccines".
NeutralizingantibodiescorrelateddirectlywiththefrequencyandqualityofBandTFHcellsbut
notwithperipheralantibodytiters,astandardtooltoassessavaccine’seffectiveness.“You
definitelyneedthosegerminalcentersandtheyhavetoworkwelltogeneratehighlyevolved,
highaffinityantibodiesthatcanneutralizethevirus,”saysHavenar-Daughton.
Goingforward,thisworkhasdemonstratedthevalueofanimportantnewtoolinvaccinetrials
forprovidingawindowintowhatitwillreallytaketomakeasuccessfulHIVvaccine,and
vaccinesagainstotherdifficultinfectiousdiseases.
ThisworkwassupportedbytheScrippsCHAVI-ID,theNationalPrimateResearchFunding(P51
RR000165/OD011132,theNationalInstituteofAllergyandInfectiousDiseases(P30-AI504),the
GatesFoundationandtheEuropeanResearchCouncil(ERC-StG-2011-280829-SHEV).
Citation:
“Directprobingofgerminalcenterresponsesrevealsimmunologicalfeaturesandbottlenecks
forneutralizingantibodyresponsestoHIVenvtrimer.”ColinHavenar-Daughton,DianeG.
Carnathan,AlbaTorrentsdelaPeña,MatthiasPauthner,BryanBriney,SamanthaM.Reiss,
JenniferS.Wood,KirtiKaushik,MaritJ.vanGils,SandyRosales,PatriciavanderWoude,
MichelaLocci,KhoaM.Le,StevenW.deTaeye,DevngSok,AtaUrRasheedMohammed,Jessica
Huang,SanjeevGumber,AnapatriciaGarcia,SudhirP.Kasturi,BaliPulendran,JohnP.Moore,
RafiAhmed,GregorySeumois,DennisR.Burton,RogierW.Sanders,GuidoSilvestri,Shane
Crotty.CellReports,2015.
DOI:http://dx.doi.org/10.1016/j.celrep.2016.10.085
AboutLaJollaInstituteforAllergyandImmunology
LaJollaInstituteforAllergyandImmunologyisdedicatedtounderstandingtheintricaciesand
poweroftheimmunesystemsothatwemayapplythatknowledgetopromotehumanhealth
andpreventawiderangeofdiseases.Sinceitsfoundingin1988asanindependent,nonprofit
researchorganization,theInstitutehasmadenumerousadvancesleadingtowardsitsgoal:life
withoutdisease®.
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