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brain sciences Review OligodendrocyteInjuryandPathogenesisof HIV-1-AssociatedNeurocognitiveDisorders HanLiu,EnquanXu, JianuoLiuandHuanguiXiong* DepartmentofPharmacologyandExperimentalNeuroscience,UniversityofNebraskaMedicalCenter,Omaha, NE68198-5880,USA;han.liu@unmc.edu(H.L.); enquan.xu@unmc.edu(E.X.); jnliu@unmc.edu(J.L.) * Correspondence: hxiong@unmc.edu;Tel.:+1-402-559-5140;Fax:+1-402-559-3744 AcademicEditor:DonnaGruol Received: 2April2016;Accepted: 20 July2016;Published: 22 July2016 Abstract: Oligodendrocytes wrap neuronal axons to form myelin, an insulating sheath which is essential for nervous impulse conduction along axons. Axonalmyelination is highly regulatedby neuronal and astrocytic signals and themaintenance ofmyelin sheaths is a very complex process. Oligodendrocytedamagecancauseaxonaldemyelinationandneuronal injury, leadingtoneurological disorders.Demyelinationinthecerebrummayproducecognitiveimpairmentinavarietyofneurological disorders, including human immunodeficiency virus type one (HIV-1)-associated neurocognitive disorders (HAND).Althoughthecombinedantiretroviral therapyhasmarkedlyreducedtheincidence ofHIV-1-associateddementia, a severe formofHAND,milder forms ofHANDremainprevalent evenwhen theperipheral viral load iswell controlled. HANDmanifests as a subcorticaldementia withdamage in thebrainwhitematter (e.g., corpuscallosum),whichconsistsofmyelinatedaxonal fibers. HowHIV-1brain infection causesmyelin injuryand resultantwhitematterdamage is an interestingareaofcurrentHIVresearch. In this review,wetentativelyaddress recentprogresson oligodendrocytedysregulationandHANDpathogenesis. Keywords:HIV-1;dementia;oligodendrocyte;myelinsheath 1. Introduction Withthe introductionofcombinedantiretroviral therapy(cART), therewasasignificantdecline inhumanimmunodeficiencyvirus typeone (HIV-1)-associatedneurocognitivedisorders (HAND). AsHIV-1-infectedpatients livea longer lifespanwithacARTregimen, it is becoming increasingly evident that theprevalenceofmilder formsofHANDseemstobeontherise [1–3].Manystudieshave revealedapreferentialdamagetosubcorticalwhitematter (e.g., corpuscallosum)intheHIV-1-infected brain, and such damage is prevalent even in the era of cART and more severe in patients with HAND[4,5].HIV-1-relatedwhitematterdamage includesdemyelinationandaxonaldysfunctionand injury. Thedemyelinationoccurswhenmyelinsheathsofneuronalaxonsare impaired in thecentral nervoussystem(CNS)orperipheralnervoussystem(PNS).Myelination, formationofmyelinsheaths byoligodendrocyteswrappingneuronal axons in theCNSor Schwanncells in thePNS, is highly regulatedbyneuronalandastrocytic signalsandmaintenanceofmyelinsheaths isacomplexprocess. Theoligodendrocyte injury isahallmark indemyelinationandwhitematterdamage. Suchdamage canbe inducedbyanalterationofgenetics,viral infections, inflammation,autoimmunity,andother unknownfactors.HIV-1-associatedoligodendrocyte/myelindamagehasbeenobservedboth incell culture [6]andpatients [7]. The earlier studies demonstrate that human polyomavirus JC (JCV) primarily causes demyelination inHIV-1-infectedbrain.ComparedtoHIV-1 infectionofastrocytesandmicroglia in the brain, JCVpredominately infectsoligodendrocytesand, thus, causesoligodendrocytedamageand furtherdemyelination.Additionally, JCVisalso themaincausative factor forprogressivemultifocal BrainSci. 2016,6, 23 116 www.mdpi.com/journal/brainsci