Download Scientists inching ever closer to HIV vaccine

ScientistsinchingeverclosertoHIVvaccine
By:BradleyFikes|December6,2016
Fordecades,successhasseemedtobeinsightforavaccinetostopthespread
ofHIV.Andfordecades,thesuccesshasproventobeanillusion.
Onceagain,newvaccinecandidatesarebeingreadiedfortrial.Andwhile
researchershavelearnedtobecautiousaboutpredictions,anever-deeper
understandingofhowHIVworkshasproducedasolidbodyofscienceonhowit
mightbethwarted.
Inafractionofthoseinfected,powerfulantibodiesthatneutralizeawidevarietyof
HIVstrainsareproduced.Unfortunately,theseneutralizingantibodiesareproduced
toolateintheinfectionprocesstostopthedisease.Butiftheimmunesystemcould
betrainedtomaketheminadvanceofinfection,intheoryHIVshouldbestoppedin
itstracks.
ScientistsatSanDiegobiomedicalinstitutionshavebeenleadersinthisintensive
effort.Andrecently,they’vediscoveredanotherimportantstepinproducinga
effectivevaccine,howtoprimetheimmunesystemtomakepowerfulantibodies
thatneutralizeabroadrangeofHIVstrains.
Thelevelsofthesebroadlyneutralizingantibodiescorrelateswiththeconditionof
certaincellsfoundinimmunetissuescalledgerminalcenters,sayresearchersledby
ShaneCrottyoftheLaJollaInstituteforAllergy&Immunology.
Germinalcentershavebeencalledthe“blackboxes”oftheimmunesystem.Theyare
thehomewhereantibody-makingcellsmatureintopotentpathogen-killing
machines.Butnobodyknowsjusthowthisprocesshappens.Andbecausethe
immunesystemconsistsofsomanycomponents,findingoutwhichpartsare
necessarytogeneratingthebroadlyneutralizingantibodiesiscritical.
Thediscoverynotonlygivescluesastowhatisgoingoninsidethemachine,it
alsoprovidesameansofcheckingwhetheravaccinecandidateisleadingthe
immunesystemdowntherightpath.
Theresearchersperformedtheirworkinrhesusmonkeys,regardedasthebest
animalmodelforthehumanimmunesystem.
ThestudywaspublishedNov.22inthejournalCellReports.Itcanbefound
at:j.mp/germinalcenter.Amongtheauthorswereotherwell-knownnamesinHIV
vaccineresearch,includingDennisR.BurtonofTheScrippsResearchInstitute,
whichhostsamajorHIVvaccineresearchcenter.Burtonandcolleagueshave
collectedbroadlyneutralizingantibodiesforyears,studyingthemtounderstand
howtheywork.
“WhilesomepeopledodevelopHIVbroadlyneutralizingantibodiesitistoolateto
behelpfultothem,”Crottysaid.“By3yearspostinfectionthevirusisfartoo
ingrained—toomanymillionsofintegratedviralgenomes—fortheantibodiesto
help.Thisisareasontheamazingantibodiesweremissedforsomanyyears,and
onlysomeoneaspersistentasDennisBurtonmanagedtofindthem.”
Crottyhasfocusedonthegerminalcenter,leadingaseriesofstudiesprobingits
function.In2013,hepublishedastudyexplainingthelinkbetween“helper”
immunecellsandtheBcellsthatmakeneutralizingantibodies.A2015
studydescribedthemechanismthatgeneratesfullyfunctional“helper”cells.
Theresearchersalsosolvedaproblemthatuntilnowhadhamperedcloser
examinationofthegerminalcenters,theinabilitytoseethemchangeovertime.
Whilelymphnodescanberemovedforbiopsies,thatcanbedoneonlyonce.But
germinalcentersmustberepeatedlymeasuredtocorrelatetheirinternalstatewith
productionofneutralizingantibodies.
Innovativeidea
TheLaJollaInstitute’sColinHavenar-Daughton,thestudy’sfirstauthor,foundthat
repeatedsamplesofgerminalcenterscouldbetakenbydrawingoutverysmall
portionsoffluid“aspirates”withfineneedles.Thismethodisoftenusedby
oncologiststoassessthestateoflymphnodes,wherecirculatingcancercellstendto
accumulate.
Thestudyprovidedaninnovativewaytotackleapreviouslyintractableproblem,
saidMarcellaFlores,associatedirectorofresearchattheAmericanFoundationfor
AIDSResearch,oramfAR,
“It’sagreatexampleoftechnologiescominginfromoutsidethefieldofHIV,”Flores
said.“It’ssomethingthatamFARisreallyinterestedin.Thestudyitselfisgreatfor
thevaccineworld.”
WhiletheabilityofneutralizingantibodiestoblockHIVisimportant,amFARwould
likeavaccinetoproduceothereffects,suchaspromptingtheimmunesystemtokill
alreadyinfectedcells,Floressaid.
“That’swhatwouldleadtoacure,”shesaid.“Whilethese(preventivevaccination)
studiesrepresentahugestepforwardinthevaccineworld,westillneedmore
informationonwhethertheprocessesthey’veidentifiedwouldleadtoacure.”
CuringHIVpresentsaparticularlydifficultchallengebecausetheviruscanhideout
inadormantform,insidethegenomeoftheimmunecellsitinfects.Whileinactive
inthegenome,it’sbeyondtheimmunesystem’sreach.Onlywheninfectedcells
beginproducingmorevirusesdoestheimmunesystemrecognizetheinfection.
SomeingeniouscurativeeffortsarenowbeingtestedonHIVpatients.Sangamo
BioSciencesofRichmond,Calif,isgeneticallyalteringimmunecellsofHIVpatients
sothecellscan’tbeinfected.Thecellsaretakenfromthepatient,genetically
modifiedandreinfused.ThetreatmentisinPhase2trials.
AsimilartrialisnowbeingcarriedoutbyTucscon-basedCalimmune,foundedby
threescientists;NobelLaureateDavidBaltimoreofCaltech;IrvinChenofUCLos
AngelesandInderM.VermaoftheSalkInstituteforBiologicalStudies.
Butinthelongterm,HIVpreventionwillbemoreeffectiveandmuchlesscostly.
Andthat’swhatCrottyandmanyotherresearchersarefocusingon.
Blockingthevirus
Vaccinesagainstsomeviruses,suchassmallpoxorpolio,canbepreparedfrom
relativelysimplederivativesofthevirus.However,HIVpresentsamuchmore
difficulttargetfortheimmunesystem.Itmutatesextremelyrapidly,andalso
presentsdecoyproteinsthatfooltheimmunesystem.HIV’svulnerableregionsare
hardtofind.
Tobeeffective,avaccinemustproduceimmunityinthevastmajorityofthosewho
arevaccinated,knownas“herdimmunity.”Whenimmunityisthatwidespread,
thosewhocan’tbevaccinatedforsomereason,suchaspregnancy,arestill
protectedfromexposuretothepathogen.
PreviouseffortstodevelopasafeandeffectiveHIVvaccine,suchasoneledbyThe
ImmuneResponseCorp.,anow-defunctCarlsbadbiotech,failedtoyieldsucha
vaccine.Thatcompany’svaccine,Remune,yieldedsomemodestsignstheimmune
systemwasbeingstimulated,butdidn’tgainapprovalbytheU.S.FoodandDrug
Administration.
GivenHIV’selusivenature,effectiveHIVneutralizingantibodiesmustbehighly
specialized.Inmostpeopleittakestheimmunesystemthreeormoreyearstomake
them.BythattimeHIViswellestablishedandifuntreated,leadstoAIDS.
Vaccineresearchersaimtospeedupthisprocessbyaseriesofimmunizationsthat
telescopetheimmuneeducationprocessintoseveralweeks.Todoso,theyneedto
understandwhatisgoingoninsidetheimmunesystem,topreparetheright
ingredientstoguideitalongtherightpath.
Togetaccesstotherhesusmonkeys,Havenar-DaughtonalliedwithDr.Guido
SilvestriandcolleaguesattheYerkesNationalPrimateResearchCenter.Usingthe
needlebiopsymethod,theystudiedthegerminalcenterresponseof12monkeys
thathadbeenimmunizedbyanHIVproteinthat’stobetestedforavaccine.
Theresearchersdiscoveredthecorrelationbetweenthecellularresponseinsidethe
germinalcenters.Unexpectedly,theyalsofoundthatthelevelsofallantibodiesin
theblooddidn’tcorrelatewithproductionofneutralizingantibodies.Thatmeant
thestrengthofthepertinentimmuneresponsewasonlyevidentfromactual
inspectionofthegerminalcenter.
Ofthe12monkeys,nineproducedneutralizingantibodies.Abetterresponseis
neededforavaccine,Havenar-DaughtonsaidinaLaJollaInstitutestatement.
“Itwasaverygoodresponsebutifyougointohumansyouwanteverybodymaking
neutralizingantibodiesandnotjustsomepeople,”hesaid.“Weneedtosolvethis
problem.”