Macrophage‐tropic HIV‐1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5

[摘要] BR‐derivedHIV‐1strainshaveanexceptionalabilitytoentermacrophagesviamechanismsinvolvingtheirgp120Envthatremainincompletelyunderstood.Here,weusedcell‐basedaffinity‐profilingmethodsandmathematicalmodelingtogeneratequantitativeVERSAmetricsthatsimultaneouslymeasureEnv‐CD4andEnv‐CCR5interactions.ThesemetricswereanalyzedtodistinguishthephenotypesofM‐tropicandnon‐M‐tropicCCR5‐usingHIV‐1variantsderivedfromautopsyBRsandLNs,respectively.WeshowthathighlyM‐tropicEnvvariantsderivedfrombraincanbedefinedbytwodistinctandsimultaneouslyoccurringphenotypes.First,BR‐derivedEnvsdemonstratedanenhancedabilitytointeractwithCD4comparedwithLN‐derivedEnvs,permittingentryintocellsexpressingscantlevelsofCD4.Second,BR‐derivedEnvsdisplayedanalteredmechanismofengagementbetweenCD4‐boundgp120andCCR5occurringintandem.Withtheuseofepitopemapping,mutagenesis,andstructuralstudies,weshowthatthisalteredmechanismischaracterizedbyincreasedexposureofCD4‐inducedepitopesingp120andbyamorecriticalinteractionbetweenBR‐derivedEnvsandtheCCR5N‐terminus,whichwasassociatedwiththepredictedpresenceofadditionalatomiccontactsformedatthegp120‐CCR5N‐terminusinterface.OurresultssuggestthatBR‐derivedHIV‐1variantswithhighlyefficientmacrophageentryadoptconformationsingp120thatsimultaneouslyalterthewayinwhichtheEnvinteractswithCD4andCCR5...

[学科分类] 生理学

[关键词] Env;Affinofile;CNS;signature;phenotype