Seite - 122 - in Advances in Neuroimmunology

BrainSci. 2016,6, 23 Most recent studies proposed that myelin injury in HAND is partially due to the effects of antiretroviral drugs on oligodendrocyte survival and differentiation. The common prescribed antiretroviraldrugs,ritonavirandlopinavir, impairboththedifferentiationofOPCsintomyelin-producing oligodendrocytesand themaintenanceofmyelinproteins invivo. Ritonavir inducesaccumulationof reactiveoxygenspecies,whicharrest theoligodendrocytedifferentiationprocess [124,125].Controversial resultswere reported inHIV-1-infected children inAfrica that significantmyelin loss in cART-naïve childrenwas observed in comparisonwith cART-treated children. However, cART-treated children alsoexhibitedasignificantmyelin loss inthecorpuscallosum[126]. Interestingly,myelin-relatedgenes encodingmyelin-associatedoligodendrocytebasicprotein,myelintranscriptionfactor1,andmyelinbasic proteinaredownregulatedinbothcART-treatedanduntreatedHANDpatients [127].Apparently, the impactofantiretroviraldrugsonoligodendrocytepathophysiologyrequires further investigation. 7. SummaryandProspects HIV-1 persists in the brain despite cART. The cART-treated subjects are not able to purge the virus from their brains and showconcomitant andpersistentwhitematter abnormalities. There are increasinginterests inunderstandinghowHIV-1causesmyelinsheath lossandwhitematterdamage inHIV-1-infectedbrains. Inthisarticle,wetrytoaddresstheclinicalandpostmortemmanifestationsof myelindamageinHANDpatientsandpossible involvementofBBBintegritydisruption,oligodendrocyte apoptosis mechanisms, and OPC regulation imbalance in HIV-1-induced oligodendrocyte/myelin abnormalities. The studies ondirect toxicity ofHIV-1viral proteins onoligodendrocytes andOPCs are emerging. As the transcriptionofHIV-1viralprotein continues in theCNS, evenwhen theviral loadisata lowlevel [128], thepersistenceof thevirusandviralproteins in thebrainhaschangedthe patternofHANDpathogenesis,bywhich inflammation,encephalitis, andneurodegenerationhave beensignificantlydecreasedbytheadventofcART. Themethods of regulationof oligodendrocyte lineage cell development arewell-established, includingtheextracellularpathways,cell tocell contact,andintracellularpathways.AsNG2+ cells are the largestpopulationofprogenitor cells in thehumanadult brain, adecreaseof absolute cell numberandproliferationofNPCandOPCmaycontribute lesstomyelindeficits inHAND.Incontrast, HIV-1-relatedOPCdifferentiationandremyelination imbalancemaybettercorrelatewithan impaired remyelination in HAND patients. The strategies for promoting axonal remyelination have been introduced especially in thosedemyelinatingdisease likemultiple sclerosis. It is anticipated that those strategies for promoting axonal remyelination in other neurodegenerative disorders can be appliedforHIV-1-associatedoligodendrocyte/myelin injury, thoughstudiesareneededtoelucidate theunderlyingmechanismsforHIV-1-associatedbrainwhitematterdamage. FurtherstudiesonunderstandingthemechanismsunderlyingHIV-1-associatedoligodendrocyte/ myelin injurymaybehamperedbythefollowingpotentialdifficulties: first,oligodendrocytesshare manycommonextracellularsignalsandintracellularsignalingpathwayswithneurons, theproposed “inside-out” and“outside-in”mechanisms for virus-induceddemyelination are indistinguishable under these conditions [42]; and, second, the pro-proliferation signals for OPC are sometimes anti-maturative [129–131]. Thiswill be a significant challenge to identify the certain timewindow to access proper remyelination invivo. Overall, promoting remyelination could be an important therapeutic strategyforHANDandotherneurodegenerativedisorders in the future. Acknowledgments:ThisworkwassupportedbyNIHgrantR01NS077873. AuthorContributions:H.L.andX.H.did literatureresearchandwrote thepaper,E.X.andJ.L.participated in literatureresearchandcontributedtodiscussion inSections6and7. Conflictsof Interest:Theauthorsdeclarenoconflictof interest. 122