Title: Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders.
Authors: Jensen, Brigid K; Monnerie, Hubert; Mannell, Maggie V; Gannon, Patrick J; Espinoza, Cagla Akay; Erickson, Michelle A; Bruce-Keller, Annadora J; Gelman, Benjamin B; Briand, Lisa A; Pierce, R Christopher; Jordan-Sciutto, Kelly L; Grinspan, Judith B
Published In J Neuropathol Exp Neurol, (2015 Nov)
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.
PubMed ID: 26469251
MeSH Terms: Adult; Animals; Animals, Newborn; Antirheumatic Agents/therapeutic use*; Cell Differentiation/drug effects; Cells, Cultured; Cognition Disorders/etiology; Cohort Studies; Disease Models, Animal; Gangliosides/metabolism; Gene Expression Regulation, Viral/drug effects*; Gene Expression Regulation, Viral/physiology; HIV Infections*/complications; HIV Infections*/drug therapy; HIV Infections*/pathology; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Myelin Basic Protein/metabolism; Myelin Proteolipid Protein/metabolism; Myelin Sheath/drug effects*; Myelin Sheath/virology; Oligodendroglia/drug effects*; Oligodendroglia/virology; Reactive Oxygen Species/metabolism