Seite - 120 - in Advances in Neuroimmunology

BrainSci. 2016,6, 23 6.MyelinMaintenanceandRemyelinationinHIV-1-InfectedBrain Repairof thedamagedmyelinsheath,which is termedremyelination, isphysiologically required tomaintainmyelinhomeostasis. Themyelin injury inneuroHIVmayalsobe inducedbyabnormalities of remyelination, inadditiontothe lossofexistingmyelinsheath.Remyelinationrequiresproliferation and survival of OPCs, migration ofOPCs to the damaged site, and development of OPCs from immature tomaturemyelinatingoligodendrocytes.HIV-1disruptsOPCdevelopment,migration,and remyelinationprocesses. 6.1.AlterationofOPCProliferationandDifferentiation inHIV-1-InfectedBrains InHIV-1-infectedbrains,milddegreesofmyelindamagewereassociatedwithan increase in oligodendrocytenumbers,an initial reactivehyperplasiawhichwasbelievedtorepresentanattempt torepairmyelindamage. Suchachangewasreversedin thepresenceofseveremyelindamage[69]. Inagreementwith theaforementionedresults,mRNAlevelsof transcriptionfactorOlig2,amarker expressedwithhigher levels inOPCsandlower levels inmatureoligodendrocytes [70], areelevated in the frontcortexofpatientswithHIVE[24], indicatinganincreaseofOPCproliferationneededfor repairingthedamagedmyelinsheath.Matureoligodendrocytedefectsarealsoobservedinanimal modelsof secondarydegeneration,whichrepresentsadditional lossofneurons,myelin,andglial cells throughtoxicevents. EarlyonsetofsecondarydegenerationtriggersOPCproliferation,but thecell numbersdecrease ina long-termdegenerative condition [71]. However, Tat exposure reduces the populationofundifferentiatedSox2+NPC(ancestorofOPC)andOlig2+OPCs,butprogenitorsurvival isunaffected[63], suggesting theproliferationwas interrupted. TatmayinhibitNPCproliferationby downregulatingcyclinD1,whichisanimportantcell cyclecomponent interactswithcyclin-dependent kinase4and6 [72]. Overall,HIV-1 infectionorviralproteinexposureappears to inclineNPCfate towardproductionofglia/astroglia at theexpenseofneuronsand/oroligodendrocytes [63,73,74]. Thus,OPCdifferentiationandmaturationare likely thekeyprocessesaffectedduringremyelination inneuroHIV. 6.2. ImbalanceofOPCDifferentiationandRemyelination inHIV-1-InfectedBrain It has been shown that differentiation ofOPCs into post-mitotic oligodendrocytes is amajor checkpoint in themyelinationprocessandsuchanoligodendrocytedifferentiation is controlledby a number of factors,many ofwhich act to inhibitmyelination, including leucine-rich repeat and immunoglobulindomain-containing-1 (LINGO-1) [75,76],Notch-1 [77,78], andWnt[79,80],whereas p38MAPK[81,82]andAKT[83]havebeenshowntoberequiredforoligodendrocytedifferentiation andmyelination.Whilemolecularmechanismsintheregulationofdevelopmentalmyelinationare discussed inexcellent reviewpaperspublishedelsewhere [84,85], thedirect interactionbetweenHIV-1 andthesemolecules remains largelyunknown. It is,however,believedthatHIV-1maydisturb the complexregulatingnetwork leadingto theremyelination imbalancebasedonthe followingfindings: (1)HIV-1alters thecell cyclebyWntsignalingpathwaysandfurther impacts thecellproliferation anddifferentiation indifferentcell types, includingperipheralbloodmononuclearcells [86],HEK293 cells [87], andastrocytes [88]; (2)HIV-1 infectionofastrocytesaltered theastrocyticWntprofileby elevatingWnt familymembers 2band10b [88]; (3) elevationof secretedWnt fromastrocytesmay negativelyregulateoligodendrocytedifferentiation inneuroHIV; (4)Notch-1signaling ispermissive forOPCexpansion,but inhibitdifferentiationandmyelin formation[89]; and(5) inKaposi’s sarcoma cells,which isaneoplasminHIV-1-infectedindividuals,overexpressionofactivatedNotch-1signaling isdetected [90]. However, toourknowledge, there isno reportyetonhowOPC/oligodendrocyte Notch-1 signaling in responding toHIV-1. Moreover, CD44, a predominant hyaluronan receptor widelyexpressed in thenervoussystem,playsanegativerole inOPCdifferentiationandmyelination. Overexpression of CD44 in precursor cells inhibits differentiation toward oligodendrocytes and promotesdifferentiation intoastrocytes, causeprogressivedemyelination inconditional transgenic 120