Attenuation of HIV‐1 replication in macrophages by cannabinoid receptor 2 agonists

[摘要] InfiltratingmonocytesandmacrophagesplayacrucialroleintheprogressionofHIV‐1infectionintheCNS.PreviousstudiesshowedthatactivationoftheCB2canattenuateinflammatoryresponsesandaffectHIV‐1infectivityinTcellsandmicroglia.Here,wereportthatCB2agonistscanalsoactasimmunomodulatorsonHIV‐1‐infectedmacrophages.First,ourfindingsindicatedthepresenceofelevatedlevelsofCB2expressiononmonocytes/macrophagesinperivascularcuffsofpostmortemHIV‐1encephaliticcases.InvitroanalysisbyFACSofprimaryhumanmonocytesrevealedastep‐wiseincreaseinCB2surfaceexpressioninmonocytes,MDMs,andHIV‐1‐infectedMDMs.Wenexttestedthenotionthatup‐regulationofCB2mayallowfortheuseofsyntheticCB2agonisttolimitHIV‐1infection.TwocommerciallyavailableCB2agonists,JWH133andGP1a,andaresorcinol‐basedCB2agonist,O‐1966,wereevaluated.ResultsfrommeasurementsofHIV‐1RTactivityintheculturemediaof7day‐infectedcellsshowedasignificantdecreaseinRTactivitywhentheCB2agonistwaspresent.Furthermore,CB2activationalsopartiallyinhibitedtheexpressionofHIV‐1pol.CB2agonistsdidnotmodulatesurfaceexpressionofCXCR4orCCR5detectedbyFACS.WespeculatethatthesefindingsindicatethatpreventionofviralentryisnotacentralmechanismforCB2‐mediatedsuppressioninviralreplication.However,CB2mayaffecttheHIV‐1replicationmachinery.Resultsfromasingle‐roundinfectionwiththepseudotypedvirusrevealedamarkeddecreaseinHIV‐1LTRactivationbytheCB2ligands.Together,theseresultsindicatethatCB2mayofferameanstolimitHIV‐1infectioninmacrophages...

[学科分类] 生理学

[关键词] neuroinflammation;JWH133;CXCR4;CCR5;encephalitis;CB2