Evolutionary and Structural Features of the C2, V3 and C3 Envelope Regions Underlying the Differences in HIV-1 and HIV-2 Biology and Infection 英文参考文献.docVIP

EvolutionaryandStructuralFeaturesoftheC2,V3and C3EnvelopeRegionsUnderlyingtheDifferencesinHIV-1 andHIV-2BiologyandInfection HelenaBarroso1,2.,PedroBorrego1.,Ine?sBa′rtolo1,2,Jose′ MariaMarcelino3,CarlosFam?′lia2 ,Alexandre Quintas2,NunoTaveira1,2,4* 1UnidadedosRetrov?′ruseInfecc?o?esAssociadas(URIA),CentrodePatoge′neseMolecular,FaculdadedeFarma′cia deLisboa,Lisboa,Portugal,2CentrodeInvestigac?a?o Interdisciplinar Egas Moniz (CiiEM), Instituto Superior de Cie?ncias da Sau′de Egas Moniz, Caparica, Portugal, 3Unidade de Tecnologia de Prote?′nas e Anticorpos Monoclonais,InstitutodeHigieneeMedicinaTropical,Lisboa,Portugal,4InstitutodeMedicinaMolecular,FaculdadedeMedicinadeLisboa,Lisboa,Portugal Abstract Background: Unlike in HIV-1 infection, the majority of HIV-2 patients produce broadly reactive neutralizing antibodies, control viral replication and survive as elite controllers. The identification of the molecular, structural and evolutionary footprints underlying these very distinct immunological and clinical outcomes may lead to the development of new strategiesforthepreventionandtreatmentofHIVinfection. Methodology/PrincipalFindings:Weperformedaside-by-sidemolecular,evolutionaryandstructuralcomparisonofthe C2,V3andC3enveloperegionsfromHIV-1andHIV-2.Theseregionscontainmajorantigenictargetsandareimportantfor receptor binding. In HIV-2, these regions also have immune modulatory properties. We found that these regions are significantlymorevariableinHIV-1thaninHIV-2.Withineachvirus,C3isthemostentropicregionfollowedbyeitherC2 (HIV-2) or V3 (HIV-1). The C3 region is well exposed in the HIV-2 envelope and is under strong diversifying selection suggestingthat,likeinHIV-1,itmayharbourneutralizingepitopes.Notably,however,extremediversificationofC2andC3 seemstobedeleteriousforHIV-2andpreventitstransmission.ComputermodellingsimulationsshowedthatinHIV-2the V3loopismuchlessexposedthanC2andC3andhasaretractileconformationduetoaphysicalinteractionwithbothC2 andC3.Theconcea