Seite - 118 - in Advances in Neuroimmunology

BrainSci. 2016,6, 23 in purifiedhumanoligodendrocytes from temporal lobe resections,HIV-1 (IIIB andBaL) infectivity wasconfirmedbydetectionofp24gagantigenandPCRamplification[33]. It iswell-knownthatHIV-1 attachesandinfectshumanhostcellsthroughCD4receptors,alongwithCXCR4andCCR5asco-receptors. TheoligodendrocytesareCD4-andCCR5-negative,butdoexpressCXCR4[31,34,35],whichdesignedly promotetheoligodendrocyteprogenitorcell(OPC)migrationandremyelination[36],andmayprovidethe anchorforHIV-1-inducedoligodendrocyteinjury.However,mostinvestigatorsagreethatHIV-1primarily infectsmicroglialcells inthebrain,butnotoligodendrocytes.HIV-1-associatedoligodendrocyte injury isbelievedtobemediatedthroughviralproteinsshedoff fromvirionsorreleasedfrominfectedother cells [9,11,12]. InHIV-1patientswithPMLcomplication,TatandJCVbotharepresentinoligodendrocytes. Tathas beenshowntosynergizewithJCV,andfacilitateof JCVgenetranscriptionandreplication, leadingto robust JCVinfection[37,38]. Tat stimulates JCVgenetranscriptionbycooperatingwithSMADproteins, the intracellular effectorsofTGF-beta, at the JCVDNAcontrol region [37]. TheeffectivenessofTat on facilitating JCVtranscriptionandreplicationvaries fromdifferentHIV-1clades [38]. SinceTat is expressed in thebrainat relativehigh levelswhile theviral loadiscontrolled inblood, thismay,at least inpart, explainwhysomeHIV-1patientsstilldevelopPMLdespitehavingagoodaccess tocART[39]. InadditiontothesynergisticeffectofTatandJCVinoligodendrocytes,cytotoxicCD8+Tcellsaggregate atdemyelinatedlesionsites in thebrain toengageJCV-infectedoligodendrocytes,whichtendtocontrol JCVdissemination,butat thecostofoligodendrocytedeathandfurtherdemyelination inPML[40]. Inaddition toTat,gp120seemstobealso involved inHIV-1-associatedoligodendrocytes/myelin injury. Ithasbeenshownthatgp120 inhibitsmyelination inratcerebralcortexculture [12]andinduces functionaldysregulationandapoptosis inculturedoligodendrocytes [11,41],which isdiscussed in asubsequent section. Inaddition to theprimaryoligodendrocyte injury,which leads to secondary axonal injury(outside-in) to furtherexacerbateneurocognitive impairments,oligodendrocyte injury canbe causedbyprimary axonopathy aswell (inside-out) [42]. The recent studyhas shown that gp120-inducedβ-APPaccumulation andaxon injury in the corpus callosumwas attenuatedbya CXCR4antagonist, examplingHIV-1 injuryofoligodendrocyte/myelinviaCXCR4[35].Althoughit isnotclearwhethergp120causessuchadetrimentaleffect throughan“outside-in”or“inside-out” mechanism,orboth,CXCR4expressed inoligodendrocytescanbeapotential target [42]. 4.AssociationbetweenBlood-BrainBarrier (BBB)DisruptionandMyelinInjury Increasing evidence indicates that myelin injury may be associated with a dysregulated blood-brainbarrier (BBB)sincemyelinpallor isoftenobservedinperivascularsectorsduringwhite matter edema[43,44]. TheBBB isa critically-protectivebarrier for thebrainandservesasahighly selective layer that separates theCNS fromthe rest of thebody. InHIV-1-infectedbrains, theBBB disruption isbelievedtobemediatedbybothviralandcellular factors, releasedfromHIV-1-infected and immune-activatedmononuclearphagocytes andendothelial cells [45,46]. The reporteddirect mechanismsunderlyingHIV-1-associatedBBBdisruptionareoftenrelatedtoalterationsofvascular tight junctions, direct toxicity of brain endothelial cells, production ofmatrixmetalloproteinases, andN-Methyl-D-Aspartate (NMDA)receptoractivation [47,48]. ThedisruptionofBBB isessential forHIV-1entrance to thebrain, resulting inbrainwhitematterdamageandconsequentneurologic deficits inpatientswithneuroHIV.Thisnotion is supportedbyanobservation thatHIV-1patients with impairedBBBshowedpoorerneurologic status thanthosewith intactBBB[49].However,myelin damagemayalsoberelatedtoBBBdisruptionwithoutHIV-1brain invasion. Inacasereport,diffuse myelinpallor inwhitematterandmassiveperivasculardilatationwereobservedinanAIDSpatient without evidence of brainHIV-1 infection, significant inflammation, ormicroglial activation [50]. Postmortem studies on the brains ofAIDSpatients revealed discretemyelin pallor areas always associatedwithcapillariesorvenules [44]. Thesefindingssuggest thatBBBbreakdownmaycontribute to theobservedoligodendrocyte/myelin/whitematter injury. 118