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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.”