Estimating Costs and Benefits of CTL Escape Mutations in SIVHIV Infection 英文参考文献.docVIP

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Estimating Costs and Benefits of CTL Escape Mutations in SIVHIV Infection 英文参考文献.doc

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Estimating Costs and Benefits of CTL Escape Mutations in SIVHIV Infection 英文参考文献

EstimatingCostsandBenefitsofCTLEscape MutationsinSIV/HIVInfection Vitaly V.Ganusov1,2*,Rob J.De Boer1 1TheoreticalBiology,UtrechtUniversity,Utrecht,Netherlands,2InstituteofBiophysics,Krasnoyarsk,Russia MutationsthatallowSIV/HIVtoavoidthecytotoxicTlymphocyte(CTL)responsearewelldocumented.Recently,there havebeenafewattemptsatestimatingthecostsofCTLescapemutationsintermsofthereductioninviralfitnessand thekillingrateatwhichtheCTLresponsespecifictooneviralepitopeclearsvirus-infectedcells.Usingamathematical modelweshowthatestimationofbothparametersdependscriticallyontheunderlyingchangesinthereplicationrate ofthevirusandthechangesinthekillingrateovertime(whichinpreviousstudieswereassumedtobeconstant).We provide a theoretical basis for estimation of these parameters using in vivo data. In particular, we show that 1) by assumingunlimitedvirusgrowthonecanobtainaminimalestimateofthefitnesscostoftheescapemutation,and2) byassumingnovirusgrowthduringtheescape,onecanobtainaminimalestimateoftheaveragekillingrate.Wealso discusstheconditionsunderwhichbetterestimatesoftheaveragekillingratecanbeobtained. Citation:GanusovVV,DeBoerRJ(2006)EstimatingcostsandbenefitsofCTLescapemutationsinSIV/HIVinfection.PLoSComputBiol2(3):e24. mutantdecreaseswithtime,iscalculated.Thesumofthetwo rates,RtE,providesanestimateoftheCTLkillingrate,or Introduction Several observations suggest that cytotoxic T lymphocyte (CTL) responses play an important role in controlling virus replicationinSIV/HIVinfections.First,depletionofCD8tT cells during chronic SIV infection of rhesus macaques leads the rate at which cells productively infected with the wild- type virus are killed by the CTL response due to the expression of the non-mutated epitope [11,12]. In the derivation of these results, the authors made an implicit assumption that the virus replicates at a constant rate, and thattherateatwhichtheCTLresponseclearsvirus-infected cells is constant, or declines slowly over time. Given recent ?ndingsontheviraldyna