Multi-Scale Modeling of HIV Infection in vitro and APOBEC3G-Based Anti-Retroviral Therapy 英文参考文献.docVIP

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Multi-Scale Modeling of HIV Infection in vitro and APOBEC3G-Based Anti-Retroviral Therapy 英文参考文献.doc

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Multi-Scale Modeling of HIV Infection in vitro and APOBEC3G-Based Anti-Retroviral Therapy 英文参考文献

Multi-ScaleModelingofHIVInfectioninvitroand APOBEC3G-BasedAnti-RetroviralTherapy IrajHosseini,FeilimMacGabhann* InstituteforComputationalMedicineandDepartmentofBiomedicalEngineering,JohnsHopkinsUniversity,Baltimore,Maryland,UnitedStatesofAmerica Abstract The human APOBEC3G is an innate restriction factor that, in the absence of Vif, restricts HIV-1 replication by inducing excessive deamination of cytidine residues in nascent reverse transcripts and inhibiting reverse transcription and integration.ToshedlightonimpactofA3G-VifinteractionsonHIVreplication,wedevelopedamulti-scalecomputational systemconsistingofintracellular(single-cell),cellularandextracellular(multicellular)eventsbyusingordinarydifferential equations. The single-cell model describes molecular-level events within individual cells (such as production and degradationofhostandviralproteins,andassemblyandreleaseofnewvirions),whereasthemulticellularmodeldescribes theviraldynamicsandmultiplecyclesofinfectionwithinapopulationofcells.Weestimatedthemodelparameterseither directlyfrompreviouslypublishedexperimentaldataorbyrunningsimulationstofindtheoptimumvalues.Wevalidated ourintegratedmodelbyreproducingtheresultsofinvitroTcellcultureexperiments.Crucially,bothdownstreameffectsof A3G(hypermutationandreductionofviralburstsize)werenecessarytoreplicatetheexperimentalresultsinsilico.Wealso used the model to study anti-HIV capability of several possible therapeutic strategies including: an antibody to Vif; upregulation of A3G; and mutated forms of A3G. According to our simulations, A3G with a mutated Vif binding site is predictedtobesignificantlymoreeffectivethanothermoleculesatthesamedose.Ultimately,weperformedsensitivity analysistoidentifyimportantmodelparameters.Theresultsshowedthatthetimingofparticleformationandvirusrelease hadthehighestimpactsonHIVreplication.ThemodelalsopredictedthatthedegradationofA3GbyVifisnotacrucialstep inHIVpathogenesis. Citation:HosseiniI,MacGabhannF(2012)Multi-ScaleModelingofHIVInfection