Seite - 117 - in Advances in Neuroimmunology

BrainSci. 2016,6, 23 leukoencephalopathy(PML),afrequentopportunisticinfectionintheCNSandacommoncomplication seen inAIDSpatients [7,8]. Recent studieshave shownthatHIV-1viralproteinsper se canact on oligodendrocytes andproduce detrimental effects, which are independent of JCV [6,9,10]. HIV-1 viralproteins, includingtheenvelopeglycoprotein120(gp120), trans-activatorof transcription(Tat), and negative regulatory factor (Nef), have been implicated inHIV-1-associated oligodendrocyte injury [9,11–14].Amongtheseviralproteins,Tathasconsistentlybeendetected inboth infectedand uninfectedoligodendrocytes in thebrainsofAIDSpatients [7], andexhibitedasynergisticdetrimental effectwith JCVorwithaddictivedrugs, suchasmorphine. In this review,we tentatively address recentprogress inHIV-1-associatedoligodendrocytepathophysiology,aimingatunderstandingthe pathogenesisofmilder formsofHAND. 2.Myelin/OligodendrocyteInjuryinHIV-1Patients Theoligodendrocyteandmyelin injuryhavebeenobservedclinically fromneurological imaging studies,serumbiochemistry,andbrainbiopsies[15–18]. Thediffusiontensormagneticresonanceimaging (DTI)promotes the investigationsofwhitematterdamage in earlyHANDandallows revealing the microstructuresofmyelinandoligodendrocytes. Thechangesofwatermolecules’diffusiveparameters inbrainwhitematterofHIV-1patients,which indicatedemyelination,havebeendetected inseveral DTIstudies[15,19,20]. ThesefindingsweresupportedbyarecentstudyonHIV-1-infectedhumanized mice that adecreased expressionofmyelin structural proteinswasobserved inwhisker barrels, the corpuscallosum,andthehippocampus,suggestingthelossofmyelinelements [21]. IntheseraandCSF ofpatientswithHAND,antibodytitersofmyelinoligodendrocyteglycoprotein(MOG),animportant myelinstructuralproteinindicatingCNS-specificautoimmunereactionforprimarydemyelination,are significantlyhigher comparedwithasymptomaticHANDpatientsandHIV-1-negativepatientswith other neurological diseases. In particular, theCSF anti-MOGantibodies exhibit a high sensitivity and specificity (85.7%and76.2%) for discriminatingpatientswith activeHANDfrom thosewith asymptomaticHAND.TheperformanceonHIVdementiascale tests is significantlyworseandthe viral loads in theCSFarehigher inMOGimmunopositiveHANDpatients thanthose inasymptomatic HANDpatients [22], suggesting thedysfunctionofoligodendrocytes is closely relatedwithHIV-1 infectionandHAND. Comparedtoastrocytes thatappear topromoterecovery inresponseof injury,oligodendrocytes have amorepassive role and tend tobedamagedas ageneral response to insults [23]. In biopsy studies, theabsolutenumberofnervefibersandaxonssignificantlydecreased inHIV-1-infectedbrain, inparticular in the frontal andoccipitalpartsof thecorpuscallosum. Themyelin sheath thickness diminishedincorpuscallosumaswell [18].Weightedgeneco-expressionnetworkanalysisshowed that theoligodendrocyte-relatedgenesareparticularlyelevated in theHIVencephalitis (HIVE)group, suggestingspecificdysfunctionof thiscell type in thosewithHIVE[24]. In HIV-1 positive patients with PML, the myelin loss is apparent both macroscopically and microscopically[25].Neuroimagingstudiesshowedthemyelinlesionsweremorefrequentlyseeninthe sub-corticalwhitematterareas[26]. PMLisbelievedtobedevelopedexclusivelyinimmunosuppressive patientswithsignificantlyhigher incidenceinpatientswithAIDS,particularly inAIDSpatientswithout cARTandwitha lowCD4+ lymphocytecount, than inpatientswithanyother immunosuppressive conditions.AlthoughcARThasdecreasedthe incidenceofPMLandimprovedpatientsurvival [27], PMLcontinues tooccur inHIV-1-positivepatientswithgoodaccess tocART,andevenwithnormal CD4+ lymphocytecounts [28,29]. ThesefindingssuggestPML-relatedoligodendrocyte/myelindamage isoften,butnotnecessarily,associatedwithsevere immunosuppressionoranimmunereconstitution inflammatorysyndrome(IRIS) in thecARTera[30]. 3. FateofOligodendrocytes inHIV-1-InfectedBrain EarlypublicationsreportedthatHIV-1cannotbedetectedinoligodendrocytes[31,32]andthismay due to the limitation ofmethodologies to identify oligodendrocytes. Dissenting resultswere found 117