Screening for and Verification of Novel Mutations Associated with Drug Resistance in the HIV Type 1subtype B′ in China 英文参考文献.docVIP

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Screening for and Verification of Novel Mutations Associated with Drug Resistance in the HIV Type 1subtype B′ in China 英文参考文献.doc

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Screening for and Verification of Novel Mutations Associated with Drug Resistance in the HIV Type 1subtype B′ in China 英文参考文献

ScreeningforandVerificationofNovelMutations AssociatedwithDrugResistanceintheHIVType 9 1subtypeB inChina HanpingLi,QingmaoGeng,WeiGuo,DaominZhuang,LinLi,YongjianLiu,ZuoyiBao,SiyangLiu, JingyunLi* DepartmentofAIDSResearch,StateKeyLaboratoryofPathogenandBiosecurity,BeijingInstituteofMicrobiologyandEpidemiology,Beijing,China Abstract Objective: Mutations associated with HIV drug resistance have been extensively characterized at the HIV-1 polymerase domain, but more studies have verified that mutations outside of the polymerase domain also results in resistance to antiviraldrugs.Inthisstudy,mutationswereidentifiedin354patientsexperiencingantiretroviraltherapy(ART)failureand in97na?¨ve-therapypatients.Mutationswhoseimpactonantiviraldrugswasunknownwereverifiedbyphenotypictesting. Methods:PolsequencesofHIVsubtypeB9obtainedfrompatientsexperiencingARTfailureandfromna?¨ve-therapypatients wereanalyzedformutationsdistinctbetweentwogroups.Mutationsthatoccurredatasignificantlyhigherfrequencyinthe ARTfailurethanthena?¨ve-therapygroupweresubmittedtotheStanfordHIVDrugResistanceDatabase(SHDB)toanalyze thecorrelationbetweenHIVmutationsanddrugresistance.Formutationswhoseimpactontheantiviraldrugresponseis unknown,thesite-directedmutagenesisapproachwasappliedtoconstructplasmidscontainingthescreenedmutations. 50% inhibitory concentration (IC50) to AZT, EFV and NVP was measured to determine the response of the genetically constructedvirusestoantiviraldrugs. Results:7mutationsat6positionsoftheRTregion,D123E,V292I,K366R,T369A,T369V,A371VandI375V,occurredmore frequently in the ART failure group than the na?¨ve-therapy group. Phenotypic characterization of these HIV mutants revealedthatconstructedviruseswithmutationsA371VandT369VexhibiteddualresistancetoAZTandEFVrespectively, whereastheother5mutationsshowedweakresistance.AlthoughtheimpactoftheothersixmutationsonresponsetoNVP wasminimal,mutationT369VcouldenhanceresistancetoNVP. Conclusions:ThisstudydemonstratedthatmutationsattheRTC-terminalin