TY - JOUR
T1 - Altered oligodendrocyte maturation and myelin maintenance
T2 - The role of antiretrovirals in HIV-associated neurocognitive disorders
AU - Jensen, Brigid K.
AU - Monnerie, Hubert
AU - Mannell, Maggie V.
AU - Gannon, Patrick J.
AU - Espinoza, Cagla Akay
AU - Erickson, Michelle A.
AU - Bruce-Keller, Annadora J.
AU - Gelman, Benjamin B.
AU - Briand, Lisa A.
AU - Pierce, R. Christopher
AU - Jordan-Sciutto, Kelly L.
AU - Grinspan, Judith B.
N1 - Publisher Copyright:
Copyright © 2015 by the American Association of Neuropathologists, Inc.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Antiretroviral
KW - HIV
KW - HIV-Associated neurocognitive Disorders
KW - Myelin
KW - Oligodendrocyte
KW - Pediatric AIDS
KW - Protease inhibitor
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U2 - 10.1097/NEN.0000000000000255
DO - 10.1097/NEN.0000000000000255
M3 - Article
C2 - 26469251
AN - SCOPUS:84945231810
SN - 0022-3069
VL - 74
SP - 1093
EP - 1118
JO - Journal of Neuropathology and Experimental Neurology
JF - Journal of Neuropathology and Experimental Neurology
IS - 11
ER -