4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms 英文参考文献.docVIP

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4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms 英文参考文献.doc

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4E10-Resistant HIV-1 Isolated from Four Subjects with Rare Membrane-Proximal External Region Polymorphisms 英文参考文献

4E10-ResistantHIV-1IsolatedfromFourSubjectswith RareMembrane-ProximalExternalRegion Polymorphisms KyleJ.Nakamura1,2,JohannesS.Gach3,LauraJones1,KatherineSemrau4,JanWalter1¤ ,Frederic Bibollet-Ruche5,JulieM.Decker5,LauraHeath6,WilliamD.Decker1,MosesSinkala7,ChipepoKankasa8, DonaldThea4,JamesMullins6,9,LouiseKuhn10,MichaelB.Zwick3,GraceM.Aldrovandi1* 1DepartmentofPediatrics,ChildrensHospitalofLosAngeles,LosAngeles,California,UnitedStatesofAmerica,2SystemsBiologyandDiseaseProgram,Universityof SouthernCaliforniaKeckSchoolofMedicine,LosAngeles,California,UnitedStatesofAmerica,3DepartmentofImmunologyandMicrobialScience,TheScrippsResearch Institute, La Jolla, California, United States of America, 4Center for International Health and Development, Boston University School of Public Health, Boston, Massachusetts,UnitedStatesofAmerica,5DepartmentofMedicine,UniversityofAlabamaatBirmingham,Birmingham,Alabama,UnitedStatesofAmerica,6Department of Microbiology, University of Washington, Seattle, Washington, United States of America, 7Lusaka District Health Management Team, Lusaka, Zambia, 8University Teaching Hospital, University of Zambia, Lusaka, Zambia, 9Department of Medicine, University of Washington, Seattle, Washington, United States of America, 10DepartmentofEpidemiology,ColumbiaUniversity,NewYork,NewYork,UnitedStatesofAmerica Abstract Human antibody 4E10 targets the highly conserved membrane-proximal external region (MPER) of the HIV-1 transmembrane glycoprotein, gp41, and has extraordinarily broad neutralizing activity. It is considered by many to be a prototype for vaccine development. In this study, we describe four subjects infected with viruses carrying rare MPER polymorphismsassociatedwithresistanceto4E10neutralization.InonecaseresistantviruscarryingaW680Gsubstitution wastransmittedfrommothertoinfant.Weusedsite-directedmutagenesistodemonstratethattheW680Gsubstitutionis necessary for conferring the 4E10-resistant phenotype, but that it is not sufficient to transf