An Evolutionary-Network Model Reveals Stratified Interactions in the V3 Loop of the HIV-1 Envelope 英文参考文献.docVIP

AnEvolutionary-NetworkModelReveals StratifiedInteractionsintheV3Loop oftheHIV-1Envelope Art F.Y.Poon1*,Fraser I.Lewis2¤,Sergei L.Kosakovsky Pond1,Simon D.W. Frost1 1DepartmentofPathology,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica, 2InstituteofEvolutionaryBiology,UniversityofEdinburgh, Edinburgh,Scotland,UnitedKingdom Thethirdvariableloop(V3)ofthehumanimmunodeficiencyvirustype1(HIV-1)envelopeisaprincipaldeterminantof antibodyneutralizationandprogressiontoAIDS.Althoughitisundoubtedlyanimportanttargetforvaccineresearch, extensive genetic variation in V3 remains an obstacle to the development of an effective vaccine. Comparative methodsthat exploit theabundance ofsequence datacandetect interactions betweenresidues ofrapidlyevolving proteins such as the HIV-1 envelope, revealing biological constraints on their variability. However, previous studies havereliedimplicitlyontwobiologicallyunrealisticassumptions:(1)thatfoundereffectsintheevolutionaryhistoryof the sequences can be ignored, and; (2) that statistical associations between residues occur exclusively in pairs. We showthatcomparativemethodsthatneglecttheevolutionaryhistoryofextantsequencesaresusceptibletoahigh rate of false positives (20%–40%). Therefore, we propose a new method to detect interactions that relaxes both of theseassumptions.First,wereconstructtheevolutionaryhistoryofextantsequencesbymaximumlikelihood,shifting focusfromextantsequencevariationtotheunderlyingsubstitutionevents.Second,weanalyzethejointdistribution ofsubstitutioneventsamongpositionsinthesequenceasaBayesiangraphicalmodel,inwhicheachbranchinthe phylogeny is a unit of observation. We perform extensive validation of our models using both simulations and a controlcaseofknowninteractionsinHIV-1protease,andapplythismethodtodetectinteractionswithinV3froma sampleof1,154HIV-1envelopesequences.Ourmethodgreatlyreducesthenumberoffalsepositivesduetofounder effects, while capturing several higher-order interacti