title: Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders.
abstract: Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals have HIV-associated neurocognitive disorders (HAND). Studies of antiretroviral-treated patients have revealed persistent white matter abnormalities including diffuse myelin pallor, diminished white matter tracts, and decreased myelin protein mRNAs. Loss of myelin can contribute to neurocognitive dysfunction because the myelin membrane generated by oligodendrocytes is essential for rapid signal transduction and axonal maintenance. We hypothesized that myelin changes in HAND are partly due to effects of antiretroviral drugs on oligodendrocyte survival and/or maturation. We showed that primary mouse oligodendrocyte precursor cell cultures treated with therapeutic concentrations of HIV protease inhibitors ritonavir or lopinavir displayed dose-dependent decreases in oligodendrocyte maturation; however, this effect was rapidly reversed after drug removal. Conversely, nucleoside reverse transcriptase inhibitor zidovudine had no effect. Furthermore, in vivo ritonavir administration to adult mice reduced frontal cortex myelin protein levels. Finally, prefrontal cortex tissue from HIV-positive individuals with HAND on cART showed a significant decrease in myelin basic protein compared with untreated HIV-positive individuals with HAND or HIV-negative controls. These findings demonstrate that antiretrovirals can impact myelin integrity and have implications for myelination in juvenile HIV patients and myelin maintenance in adults on lifelong therapy.
authors.affiliation: From the Department of Neuroscience, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (BKJ, MVM); Department of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (BKJ, HM, JBG); Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (BKJ, PJG, CAE, MAE, KLJ-S); Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana (AJB-K); Department of Pathology, University of Texas Medical Branch, Galveston, Texas (BBG) Department of Psychology, College of Liberal Arts, Temple University, Philadelphia, Pennsylvania (LAB); Center for Neurobiology and Behavior, Department of Psychiatry, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (CP).
authors.forename: Brigid K
authors.initials: BK
authors.lastname: Jensen
authors.forename: Hubert
authors.initials: H
authors.lastname: Monnerie
authors.forename: Maggie V
authors.initials: MV
authors.lastname: Mannell
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Gannon
authors.forename: Cagla Akay
authors.initials: CA
authors.lastname: Espinoza
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Erickson
authors.forename: Annadora J
authors.initials: AJ
authors.lastname: Bruce-Keller
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Gelman
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Briand
authors.forename: R Christopher
authors.initials: RC
authors.lastname: Pierce
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Jordan-Sciutto
authors.forename: Judith B
authors.initials: JB
authors.lastname: Grinspan
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000209:etiology; D015331:Cohort Studies; D004195:Disease Models, Animal; D005732:Gangliosides / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000187:drug effects* / Q000502:physiology; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D004676:Myelin Basic Protein / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects* / Q000821:virology; D009836:Oligodendroglia / Q000187:drug effects* / Q000821:virology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; D005732:Gangliosides; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse; D017382:Reactive Oxygen Species; C062875:ganglioside A2B5