Retinoblastoma protein induction by HIV viremia or CCR5 in monocytes exposed to HIV‐1 mediates protection from activation‐induced apoptosis: ex vivo and in vitro study

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: inflammation;    autophagy;    chemokines;    p53;    p21;    Beclin;   

DOI  :  10.1189/jlb.1111552

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Wehavepreviouslydescribedanantiapoptoticsteady‐stategeneexpressionprofileincirculatinghumanmonocytesfromasymptomaticviremicHIV+donors,butthemechanismassociatedwiththisapoptosisresistanceremainstobefullyelucidated.Here,weshowthatRb1activationisadominantfeatureofapoptosisresistanceinmonocytesexposedtoHIV‐1invivo(asmeasuredexvivo)andinvitro.MonocytesfromasymptomaticviremicHIV+individualsshowapositivecorrelationbetweenlevelsofhypophosphorylated(active)Rb1andVLinconjunctionwithincreasesinotherp53‐inducibleproteinsassociatedwithantiapoptosisregulation,suchasp21andPAI‐1(SERPINE1),whencomparedwithcirculatingmonocytesfromuninfecteddonors.MonocytesexposedinvitrotoHIV‐1R5isolatesbutnotX4isolatesshowedlowercaspase‐3activationafterapoptosisinduction,indicatingarolefortheCCR5signalingpathway.Moreover,monocytesexposedtoR5HIV‐1orMIP‐1βinducedRb1andp21expressionandanaccumulationofautophagymarkers,LC3andBeclin.TheinhibitionofRb1activityinHIV‐1R5viral‐exposedmonocytesusingsiRNAledtoincreasedapoptosissensitivity,therebyconfirmingacentralroleforRb1intheantiapoptoticphenotype.OurdataidentifyRb1inductioninchronicasymptomaticHIV‐1infectionasamediatorofapoptosisresistanceinmonocytesinassociationwithprotectiveautophagyandcontributingtomonocytesurvivalduringimmuneactivationand/orHIV‐1viremia...

【 授权许可】

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