Adeno-associated virus - Wikipedia

Adeno-associated viruses (AAV) are small viruses that infect humans and some other primate species. They belong to the genus Dependoparvovirus, ... Adeno-associatedvirus FromWikipedia,thefreeencyclopedia Jumptonavigation Jumptosearch Speciesofvirus Adeno-associatedvirus Adeno-associatedvirusserotype2structurefrom1LP3.Onefivefoldaxisshowncenter. Scientificclassification (unranked): Virus Realm: Monodnaviria Kingdom: Shotokuvirae Phylum: Cossaviricota Class: Quintoviricetes Order: Piccovirales Family: Parvoviridae Subfamily: Parvovirinae Genus: Dependoparvovirus Virusesincluded: Adeno-associateddependoparvovirusA Adeno-associateddependoparvovirusB Adeno-associatedviruses(AAV)aresmallvirusesthatinfecthumansandsomeotherprimatespecies.TheybelongtothegenusDependoparvovirus,whichinturnbelongstothefamilyParvoviridae.Theyaresmall(20nm)replication-defective,nonenvelopedvirusesandhavelinearsingle-strandedDNA(ssDNA)genomeofapproximately4.8kilobases(kb).[1][2] AAVarenotcurrentlyknowntocausedisease.Thevirusescauseaverymildimmuneresponse.SeveraladditionalfeaturesmakeAAVanattractivecandidateforcreatingviralvectorsforgenetherapy,andforthecreationofisogenichumandiseasemodels.[3]GenetherapyvectorsusingAAVcaninfectbothdividingandquiescentcellsandpersistinanextrachromosomalstatewithoutintegratingintothegenomeofthehostcell.Inthenativevirus,however,integrationofvirallycarriedgenesintothehostgenomedoesoccur.[4]Integrationcanbeimportantforcertainapplications,butcanalsohaveunwantedconsequences.RecenthumanclinicaltrialsusingAAVforgenetherapyintheretinahaveshownpromise.[5] Contents 1History 2Useingenetherapy 2.1Advantagesanddrawbacks 2.2Clinicaltrials 3FundamentalBiology 3.1Genomics,transcriptomicsandproteomics 3.1.1ITRsequences 3.1.2repgeneandRepproteins 3.1.3capgeneandVPproteins 3.1.4Post-translationalmodifications 4Classification,serotypes,receptorsandnativetropism 4.1Serotype2 4.2Otherserotypes 4.2.1Syntheticserotypes 5Immunology 5.1Innate 5.2Humoral 5.3Cell-mediated 6Infectioncycle 7Seealso 8References 9Externallinks History[edit] Theadeno-associatedvirus(AAV),previouslythoughttobeacontaminantinadenoviruspreparations,wasfirstidentifiedasadependoparvovirusinthe1960sinthelaboratoriesofBobAtchisonatPittsburghandWallaceRoweatNIH.Serologicalstudiesinhumanssubsequentlyindicatedthat,despitebeingpresentinpeopleinfectedbyhelpervirusessuchasadenovirusorherpesvirus,AAVitselfdidnotcauseanydisease.[6] Useingenetherapy[edit] Advantagesanddrawbacks[edit] Wild-typeAAVhasattractedconsiderableinterestfromgenetherapyresearchersduetoanumberoffeatures.Chiefamongsttheseisthevirus'sapparentlackofpathogenicity.Itcanalsoinfectnon-dividingcellsandhastheabilitytostablyintegrateintothehostcellgenomeataspecificsite(designatedAAVS1)inthehumanchromosome19.[7][8]Thisfeaturemakesitsomewhatmorepredictablethanretroviruses,whichpresentthethreatofarandominsertionandofmutagenesis,whichissometimesfollowedbydevelopmentofacancer.TheAAVgenomeintegratesmostfrequentlyintothesitementioned,whilerandomincorporationsintothegenometakeplacewithanegligiblefrequency.DevelopmentofAAVsasgenetherapyvectors,however,haseliminatedthisintegrativecapacitybyremovaloftherepandcapfromtheDNAofthevector.Thedesiredgenetogetherwithapromotertodrivetranscriptionofthegeneisinsertedbetweentheinvertedterminalrepeats(ITRs)thataidinconcatemerformationinthenucleusafterthesingle-strandedvectorDNAisconvertedbyhostcellDNApolymerasecomplexesintodouble-strandedDNA.AAV-basedgenetherapyvectorsformepisomalconcatemersinthehostcellnucleus.Innon-dividingcells,theseconcatemersremainintactforthelifeofthehostcell.Individingcells,AAVDNAislostthroughcelldivision,sincetheepisomalDNAisnotreplicatedalongwiththehostcellDNA.[9]RandomintegrationofAAVDNAintothehostgenomeisdetectablebutoccursatverylowfrequency.[9]AAVsalsopresentverylowimmunogenicity,seeminglyrestrictedtogenerationofneutralizingantibodies,whiletheyinducenoclearlydefinedcytotoxicresponse.[10][11][12]Thisfeature,alongwiththeabilitytoinfectquiescentcellspresenttheirdominanceoveradenovirusesasvectorsforhumangenetherapy. Useofthevirusdoespresentsomedisadvantages.Thecloningcapacityofthevectorisrelativelylimitedandmosttherapeuticgenesrequirethecompletereplacementofthevirus's4.8kilobasegenome.Largegenesare,therefore,notsuitableforuseinastandardAAVvector.Optionsarecurrentlybeingexploredtoovercomethelimitedcodingcapacity.[13]TheAAVITRsoftwogenomescanannealtoformhead-to-tailconcatemers,almostdoublingthecapacityofthevector.InsertionofsplicesitesallowsfortheremovaloftheITRsfromthetranscript. BecauseofAAV'sspecializedgenetherapyadvantages,researchershavecreatedanalteredversionofAAVtermedself-complementaryadeno-associatedvirus(scAAV).WhereasAAVpackagesasinglestrandofDNAandmustwaitforitssecondstrandtobesynthesized,scAAVpackagestwoshorterstrandsthatarecomplementarytoeachother.Byavoidingsecond-strandsynthesis,scAAVcanexpressmorequickly,althoughasacaveat,scAAVcanonlyencodehalfofthealreadylimitedcapacityofAAV.[14]RecentreportssuggestthatscAAVvectorsaremoreimmunogenicthansinglestrandedadenovirusvectors,inducingastrongeractivationofcytotoxicTlymphocytes.[15] Humoralimmunityinstigatedbyinfectionwiththewildtypeisthoughttobecommon.TheassociatedneutralisingactivitylimitstheusefulnessofthemostcommonlyusedserotypeAAV2incertainapplications.Accordingly,themajorityofclinicaltrialsunderwayinvolvedeliveryofAAV2intothebrain,arelativelyimmunologicallyprivilegedorgan.Inthebrain,AAV2isstronglyneuron-specific. Clinicaltrials[edit] Asof2019,AAVvectorshavebeenusedinover250clinicaltrialsworldwide,approximately8.3%ofvirus-vectoredgene-therapytrials.[16]Recently,promisingresultshavebeenobtainedfromPhase1andPhase2trialsforanumberofdiseases,includingLeber'scongenitalamaurosis,[5][17][18]hemophilia,[19]congestiveheartfailure,[20]spinalmuscularatrophy,[21]lipoproteinlipasedeficiency,[22]andParkinson'sdisease.[23] SelectedclinicaltrialsusingAAV-basedvectors[24] Indication Gene Routeofadministration Phase Subjectnumber Status Cysticfibrosis CFTR Lung,viaaerosol I 12 Complete CFTR Lung,viaaerosol II 38 Complete CFTR Lung,viaaerosol II 100 Complete HemophiliaB FIX Intramuscular I 9 Complete FIX Hepaticartery I 6 Ended Arthritis TNFR:Fc Intraarticular I 1 Ongoing Hereditaryemphysema AAT Intramuscular I 12 Ongoing Leber'scongenitalamaurosis RPE65 Subretinal I–II Multiple Severalongoingandcomplete(voretigeneneparvovec) Age-relatedmaculardegeneration sFlt-1 Subretinal I–II 24 Ongoing Duchennemusculardystrophy SGCA Intramuscular I 10 Ongoing Parkinson'sdisease GAD65,GAD67 Intracranial I 12 Complete[25] Canavandisease AAC Intracranial I 21 Ongoing Battendisease CLN2 Intracranial I 10 Ongoing Alzheimer'sdisease NGF Intracranial I 6 Ongoing Spinalmuscularatrophy SMN1 Intravenous,intrathecal I–III 150+ Severalongoingandcomplete(onasemnogeneabeparvovec) Congestiveheartfailure SERCA2a Intra-coronary IIb 250 Ongoing FundamentalBiology[edit] Twoadenovirusparticlessurroundedbynumerous,smalleradeno-associatedviruses(negative-stainingelectronmicroscopy,magnificationapproximately200,000×) Genomics,transcriptomicsandproteomics[edit] TheAAVgenomeisbuiltofsingle-strandeddeoxyribonucleicacid(ssDNA),eitherpositive-ornegative-sensed,whichisabout4.7kilobaselong.ThegenomecomprisesITRsatbothendsoftheDNAstrand,andtwoopenreadingframes(ORFs):repandcap.TheformeriscomposedoffouroverlappinggenesencodingRepproteinsrequiredfortheAAVlifecycle,andthelattercontainsoverlappingnucleotidesequencesofcapsidproteins:VP1,VP2andVP3,whichinteracttoformacapsidwithicosahedralsymmetry.[26] ITRsequences[edit] Theinvertedterminalrepeat(ITR)sequencescomprise145baseseach.Theywerenamedsobecauseoftheirsymmetry,whichwasshowntoberequiredforefficientmultiplicationoftheAAVgenome.[27]Thefeatureofthesesequencesthatgivesthemthispropertyistheirabilitytoformahairpin,whichcontributestoso-calledself-primingthatallowsprimase-independentsynthesisofthesecondDNAstrand.TheITRswerealsoshowntoberequiredforbothintegrationoftheAAVDNAintothehostcellgenome(19thchromosomeinhumans)andrescuefromit,[28][29]aswellasforefficientencapsidationoftheAAVDNAcombinedwithgenerationofafullyassembled,deoxyribonuclease-resistantAAVparticles.[30] Withregardtogenetherapy,ITRsseemtobetheonlysequencesrequiredincisnexttothetherapeuticgene:structural(cap)andpackaging(rep)proteinscanbedeliveredintrans.WiththisassumptionmanymethodswereestablishedforefficientproductionofrecombinantAAV(rAAV)vectorscontainingareporterortherapeuticgene.However,itwasalsopublishedthattheITRsarenottheonlyelementsrequiredincisfortheeffectivereplicationandencapsidation.Afewresearchgroupshaveidentifiedasequencedesignatedcis-actingRep-dependentelement(CARE)insidethecodingsequenceoftherepgene.CAREwasshowntoaugmentthereplicationandencapsidationwhenpresentincis.[31][32][33][34] repgeneandRepproteins[edit] Onthe"leftside"ofthegenometherearetwopromoterscalledp5andp19,fromwhichtwooverlappingmessengerribonucleicacids(mRNAs)ofdifferentlengthcanbeproduced.Eachofthesecontainsanintronwhichcanbeeithersplicedoutornot.Giventhesepossibilities,fourvariousmRNAs,andconsequentlyfourvariousRepproteinswithoverlappingsequencecanbesynthesized.Theirnamesdepicttheirsizesinkilodaltons(kDa):Rep78,Rep68,Rep52andRep40.[35]Rep78and68canspecificallybindthehairpinformedbytheITRintheself-primingactandcleaveataspecificregion,designatedterminalresolutionsite,withinthehairpin.TheywerealsoshowntobenecessaryfortheAAVS1-specificintegrationoftheAAVgenome.AllfourRepproteinswereshowntobindATPandtopossesshelicaseactivity.Itwasalsoshownthattheyupregulatethetranscriptionfromthep40promoter(mentionedbelow),butdownregulatebothp5andp19promoters.[29][35][36][37][38][39] capgeneandVPproteins[edit] Therightsideofapositive-sensedAAVgenomeencodesoverlappingsequencesofthreecapsidproteins,VP1,VP2andVP3,whichstartfromonepromoter,designatedp40.Themolecularweightsoftheseproteinsare87,72and62kiloDaltons,respectively.[40]TheAAVcapsidiscomposedofamixtureofVP1,VP2,andVP3totaling60monomersarrangedinicosahedralsymmetryinaratioof1:1:10,[41]withanemptymassofapproximately3.8MDa.[42] ThecrystalstructureoftheVP3proteinwasdeterminedbyXie,Bue,etal.[43] AAV2capsid,shownasaribbondiagram,withthebackhalfhiddenforclarity.Onefivefoldsymmetryaxisisshowncenter. Thecapgeneproducesanadditional,non-structuralproteincalledtheAssembly-ActivatingProtein(AAP).ThisproteinisproducedfromORF2andisessentialforthecapsid-assemblyprocess.[44]Theexactfunctionofthisproteinintheassemblyprocessanditsstructurehavenotbeensolvedtodate. AllthreeVPsaretranslatedfromonemRNA.AfterthismRNAissynthesized,itcanbesplicedintwodifferentmanners:eitheralongerorshorterintroncanbeexcisedresultingintheformationoftwopoolsofmRNAs:a2.3kb-anda2.6kb-longmRNApool.Usually,especiallyinthepresenceofadenovirus,thelongerintronispreferred,sothe2.3-kb-longmRNArepresentstheso-called"majorsplice".InthisformthefirstAUGcodon,fromwhichthesynthesisofVP1proteinstarts,iscutout,resultinginareducedoveralllevelofVP1proteinsynthesis.ThefirstAUGcodonthatremainsinthemajorspliceistheinitiationcodonforVP3protein.However,upstreamofthatcodoninthesameopenreadingframeliesanACGsequence(encodingthreonine)whichissurroundedbyanoptimalKozakcontext.ThiscontributestoalowlevelofsynthesisofVP2protein,whichisactuallyVP3proteinwithadditionalNterminalresidues,asisVP1.[45][46][47][48] Sincethebiggerintronispreferredtobesplicedout,andsinceinthemajorsplicetheACGcodonisamuchweakertranslationinitiationsignal,theratioatwhichtheAAVstructuralproteinsaresynthesizedinvivoisabout1:1:20,whichisthesameasinthematurevirusparticle.[49]TheuniquefragmentattheNterminusofVP1proteinwasshowntopossessthephospholipaseA2(PLA2)activity,whichisprobablyrequiredforthereleasingofAAVparticlesfromlateendosomes.[50]Muralidharetal.reportedthatVP2andVP3arecrucialforcorrectvirionassembly.[47]Morerecently,however,Warringtonetal.showedVP2tobeunnecessaryforthecompletevirusparticleformationandanefficientinfectivity,andalsopresentedthatVP2cantoleratelargeinsertionsinitsNterminus,whileVP1cannot,probablybecauseofthePLA2domainpresence.[51] Post-translationalmodifications[edit] Recentdiscoveriesmadethroughuseofhigh-throughput'omicsapproachesincludethefactthatAAVcapsidsarepost-translationallymodified(PTM)duringproductionsuchasacetylation,methylation,phosphorylation,deamidation,O-GlycNAcylation[52]andSUMOylationthroughoutcapsidproteinsVP1,VP2andVP3.ThesePTMsdifferdependingonthemanufacturingproductionplatform.AnothersuchdiscoveryisthefactthatAAVgenomesareepigeneticallymethylatedduringproduction.Besidesprice,thesefindingsmightaffectexpressionkinetics,rAAVreceptorbinding,trafficking,vectorimmunogenicity,andexpressiondurability.[53][54] Classification,serotypes,receptorsandnativetropism[edit] TwospeciesofAAVwererecognisedbytheInternationalCommitteeonTaxonomyofVirusesin2013:adeno-associateddependoparvovirusA(formerlyAAV-1,-2,-3and-4)andadeno-associateddependoparvovirusB(formerlyAAV-5).[55][56] Untilthe1990s,virtuallyallAAVbiologywasstudiedusingAAVserotype2.However,AAVishighlyprevalentinhumansandotherprimatesandseveralserotypeshavebeenisolatedfromvarioustissuesamples.Serotypes2,3,5,and6werediscoveredinhumancells,AAVserotypes1,4,and7–11innonhumanprimatesamples.[57]Asof2006therehavebeen11AAVserotypesdescribed,the11thin2004.[58]AAVcapsidproteinscontain12hypervariablesurfaceregions,withmostvariabilityoccurringinthethreefoldproximalpeaks,buttheparvovirusgenomeingeneralpresentshighlyconservedreplicationandstructuralgenesacrossserotypes.[57]Alloftheknownserotypescaninfectcellsfrommultiplediversetissuetypes.TissuespecificityisdeterminedbythecapsidserotypeandpseudotypingofAAVvectorstoaltertheirtropismrangewilllikelybeimportanttotheiruseintherapy. Serotype2[edit] Serotype2(AAV2)hasbeenthemostextensivelyexaminedsofar.[59][60][61][62][63][64]AAV2presentsnaturaltropismtowardsskeletalmuscles,[65]neurons,[59]vascularsmoothmusclecells[66]andhepatocytes.[67] ThreecellreceptorshavebeendescribedforAAV2:heparansulfateproteoglycan(HSPG),aVβ5integrinandfibroblastgrowthfactorreceptor1(FGFR-1).Thefirstfunctionsasaprimaryreceptor,whilethelattertwohaveaco-receptoractivityandenableAAVtoenterthecellbyreceptor-mediatedendocytosis.[68][69][70]ThesestudyresultshavebeendisputedbyQiu,Handa,etal.[71]HSPGfunctionsastheprimaryreceptor,thoughitsabundanceintheextracellularmatrixcanscavengeAAVparticlesandimpairtheinfectionefficiency.[72] Studieshaveshownthatserotype2ofthevirus(AAV-2)apparentlykillscancercellswithoutharminghealthyones."Ourresultssuggestthatadeno-associatedvirustype2,whichinfectsthemajorityofthepopulationbuthasnoknownilleffects,killsmultipletypesofcancercellsyethasnoeffectonhealthycells,"saidCraigMeyers,[73]aprofessorofimmunologyandmicrobiologyatthePennStateCollegeofMedicineinPennsylvaniain2005.[74]Thiscouldleadtoanewanti-canceragent. Otherserotypes[edit] AlthoughAAV2isthemostpopularserotypeinvariousAAV-basedresearch,ithasbeenshownthatotherserotypescanbemoreeffectiveasgenedeliveryvectors.ForinstanceAAV6appearsmuchbetterininfectingairwayepithelialcells,[75][76]AAV7presentsveryhightransductionrateofmurineskeletalmusclecells(similartoAAV1andAAV5),AAV8issuperbintransducinghepatocytes[77][78][79]andAAV1and5wereshowntobeveryefficientingenedeliverytovascularendothelialcells.[80]Inthebrain,mostAAVserotypesshowneuronaltropism,whileAAV5alsotransducesastrocytes.[81]AAV6,ahybridofAAV1andAAV2,[79]alsoshowslowerimmunogenicitythanAAV2.[78] Serotypescandifferwiththerespecttothereceptorstheyareboundto.Forexample,AAV4andAAV5transductioncanbeinhibitedbysolublesialicacids(ofdifferentformforeachoftheseserotypes),[82]andAAV5wasshowntoentercellsviatheplatelet-derivedgrowthfactorreceptor.[83] Syntheticserotypes[edit] TherehavebeenmanyeffortstoengineerandimprovenewAAVvariantsforbothclinicalandresearchpurposes.Suchmodificationsincludenewtropismstotargetspecifictissues,andmodifiedsurfaceresiduestoevadedetectionbytheimmunesystem.BeyondoptingforparticularstrainsofrecombinantAAV(rAAV)totargetparticularcells,researchershavealsoexploredAAVpseudotyping,thepracticeofcreatinghybridsofcertainAAVstrainstoapproachanevenmorerefinedtarget.Thehybridiscreatedbytakingacapsidfromonestrainandthegenomefromanotherstrain.Forexample,researchinvolvingAAV2/5,ahybridwiththegenomeofAAV2andthecapsidofAAV5,wasabletoachievemoreaccuracyandrangeinbraincellsthanAAV2wouldbeabletoachieveunhybridized.Researchershavecontinuedtoexperimentwithpseudotypingbycreatingstrainswithhybridcapsids.AAV-DJhasahybridcapsidfromeightdifferentstrainsofAAV;assuch,itcaninfectdifferentcellsthroughoutmanyareasofthebody,apropertywhichasinglestrainofAAVwithalimitedtropismwouldnothave.[84]OthereffortstoengineerandimprovenewAAVvariantshaveinvolvedtheancestralreconstructionofvirusvariantstogeneratenewvectorswithenhancedpropertiesforclinicalapplicationsandthestudyofAAVbiology.[85] Immunology[edit] AAVisofparticularinteresttogenetherapistsduetoitsapparentlimitedcapacitytoinduceimmuneresponsesinhumans,afactorwhichshouldpositivelyinfluencevectortransductionefficiencywhilereducingtheriskofanyimmune-associatedpathology. AAVisnotconsideredtohaveanyknownroleindisease.[86]However,hostimmunesystemresponseandimmunetolerancereducetheefficacyofAAV-mediatedgenetherapy.HostimmuneresponsehasbeenshowntorespondtotheAAVvectors,thetransducedcells,andthetransducedproteins.[87]Theimmuneresponsecanbesubdividedintotwocategories:innateandadaptive,thelatterofwhichisdividedintohumoralandcell-mediated.[88][89] Innate[edit] TheinnateimmuneresponsetotheAAVvectorshasbeencharacterisedinanimalmodels.Intravenousadministrationinmicecausestransientproductionofpro-inflammatorycytokinesandsomeinfiltrationofneutrophilsandotherleukocytesintotheliver,whichseemstosequesteralargepercentageoftheinjectedviralparticles.Bothsolublefactorlevelsandcellinfiltrationappeartoreturntobaselinewithinsixhours.Bycontrast,moreaggressivevirusesproduceinnateresponseslasting24hoursorlonger.[90] In-vivostudiesindicatethatAAVvectorsinteractwiththeToll-likereceptor(TLR)9-andTLR2-MyD88pathwaystotriggertheinnateimmuneresponsebystimulatingtheproductionofinterferons.[91]It'sshownthatmicedeficientinTLR9aremorereceptivetoAAVtreatmentanddemonstratehigherlevelsoftransgeneexpression[92] Humoral[edit] Duetopreviousnaturalinfection,manypeoplehavepreexistingneutralizingantibodies(NAbs)againstAAV's,whichcansignificantlyhinderitsapplicationingenetherapy.[93]EventhoughAAV'sarehighlyvariableamongwild-typeandsyntheticvariants,antibodyrecognitionsitesmaybeconservedevolutionarily.[94] Thevirusisknowntoinstigaterobusthumoralimmunityinanimalmodelsandinthehumanpopulation,whereupto80%ofindividualsarethoughttobeseropositiveforAAV2.Antibodiesareknowntobeneutralising,andforgenetherapyapplicationsthesedoimpactonvectortransductionefficiencyviasomeroutesofadministration.AswellaspersistentAAVspecificantibodylevels,itappearsfrombothprime-booststudiesinanimalsandfromclinicaltrialsthattheB-cellmemoryisalsostrong.[95]Inseropositivehumans,circulatingIgGantibodiesforAAV2appeartobeprimarilycomposedoftheIgG1andIgG2subclasses,withlittleornoIgG3orIgG4present.[96] Cell-mediated[edit] Thecell-mediatedresponsetothevirusandtovectorsispoorlycharacterised,andhasbeenlargelyignoredintheliteratureasrecentlyas2005.[95]ClinicaltrialsusinganAAV2-basedvectortotreathaemophiliaBseemtoindicatethattargeteddestructionoftransducedcellsmaybeoccurring.[97]CombinedwithdatathatshowsthatCD8+T-cellscanrecogniseelementsoftheAAVcapsidinvitro,[98]itappearsthattheremaybeacytotoxicTlymphocyteresponsetoAAVvectors.CytotoxicresponseswouldimplytheinvolvementofCD4+ThelpercellsintheresponsetoAAVandinvitrodatafromhumanstudiessuggeststhatthevirusmayindeedinducesuchresponses,includingbothTh1andTh2memoryresponses.[96]AnumberofcandidateTcellstimulatingepitopeshavebeenidentifiedwithintheAAVcapsidproteinVP1,whichmaybeattractivetargetsformodificationofthecapsidifthevirusistobeusedasavectorforgenetherapy.[96][97] Infectioncycle[edit] ThereareseveralstepsintheAAVinfectioncycle,frominfectingacelltoproducingnewinfectiousparticles:[citationneeded] attachmenttothecellmembrane receptor-mediatedendocytosis endosomaltrafficking escapefromthelateendosomeorlysosome translocationtothenucleus uncoating formationofdouble-strandedDNAreplicativeformoftheAAVgenome expressionofrepgenes genomereplication expressionofcapgenes,synthesisofprogenyssDNAparticles assemblyofcompletevirions,and releasefromtheinfectedcell. Someofthesestepsmaylookdifferentinvarioustypesofcells,which,inpart,contributestothedefinedandquitelimitednativetropismofAAV.Replicationoftheviruscanalsovaryinonecelltype,dependingonthecell'scurrentcellcyclephase.[99] Thecharacteristicfeatureoftheadeno-associatedvirusisadeficiencyinreplicationandthusitsinabilitytomultiplyinunaffectedcells.Adeno-associatedvirusspreadsbyco-infectingacellwithahelpervirus.ThefirsthelpervirusthatwasdescribedasprovidingsuccessfulgenerationofnewAAVparticles,wastheadenovirus,fromwhichtheAAVnameoriginated.ItwasthenshownthatAAVreplicationcanbefacilitatedbyselectedproteinsderivedfromtheadenovirusgenome,[100][101]byothervirusessuchasHSV[102]orvaccinia,orbygenotoxicagents,suchasUVirradiationorhydroxyurea.[103][104][105]Dependingonthepresenceorabsenceofahelpervirus,thelifecycleofAAVfollowseitheralyticorlysogenicpathway,respectively.[106]Ifthereisahelpervirus,AAV'sgeneexpressionactivates,allowingthevirustoreplicateusingthehostcell'spolymerase.Whenthehelperviruskillsthehostcell,thenewAAVvirionsarereleased.Ifthereisnotahelperviruspresent,AAVexhibitslysogenicbehavior.WhenAAVinfectsacellalone,itsgeneexpressionisrepressed(AAVdoesnotreplicate),anditsgenomeisincorporatedintothehostgenome(intohumanchromosome19).Inrarecases,lysiscanoccurwithoutahelpervirus,butusuallyAAVcannotreplicateandkillacellonitsown.[107] Theminimalsetoftheadenoviralgenesrequiredforefficientgeneration,ofprogenyAAVparticles,wasdiscoveredbyMatsushita,Ellingeretal.[100]ThisdiscoveryallowedfornewproductionmethodsofrecombinantAAV,whichdonotrequireadenoviralco-infectionoftheAAV-producingcells.Intheabsenceofhelpervirusorgenotoxicfactors,AAVDNAcaneitherintegrateintothehostgenomeorpersistinepisomalform.IntheformercaseintegrationismediatedbyRep78andRep68proteinsandrequiresthepresenceofITRsflankingtheregionbeingintegrated.Inmice,theAAVgenomehasbeenobservedpersistingforlongperiodsoftimeinquiescenttissues,suchasskeletalmuscles,inepisomalform(acircularhead-to-tailconformation).[108] Seealso[edit] Virusesportal Isogenichumandiseasemodels OncolyticAAV RecombinantAAVmediatedgenomeengineering References[edit] ^Naso,MichaelF.;Tomkowicz,Brian;Perry,WilliamL.;Strohl,WilliamR.(2017)."Adeno-AssociatedVirus(AAV)asaVectorforGeneTherapy".BioDrugs.31(4):317–334.doi:10.1007/s40259-017-0234-5.ISSN 1173-8804.PMC 5548848.PMID 28669112. 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Externallinks[edit] KimballJW(17May2015)."GeneTherapyII".Kimball'sBiologyPages.Archivedfromtheoriginalon18March2005.Retrieved13May2005. "Adeno-associatedvirus".NCBITaxonomyBrowser.272636. 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