Protease Inhibitors, Saquinavir and Darunavir, Inhibit Oligodendrocyte Maturation: Implications for Lysosomal Stress
Despite the introduction of antiretroviral (ARV) therapy (ART), approximately 30–50% of people living with human immunodeficiency virus-1 (HIV-1) will develop a spectrum of measurable neurocognitive dysfunction, collectively called HIV-associated neurocognitive disorder (HAND). While the clinical manifestations of HAND have changed with the advent of ART, certain pathological features have endured, including white matter alterations and dysfunction. The persistence of white matter alterations in the post-ART era suggests that ARV drugs themselves may contribute to HAND pathology. Our group has previously demonstrated that two ARV compounds from the protease inhibitor (PI) class, ritonavir and lopinavir, inhibit oligodendrocyte maturation and myelin protein production. We hypothesized that other members of the PI class, saquinavir and darunavir, could also negatively impact oligodendrocyte differentiation. Here we demonstrate that treating primary rat oligodendrocyte precursor cells with therapeutically relevant concentrations of either ARV drug results in a concentration-dependent inhibition of oligodendrocyte maturation in vitro. Furthermore, we show that acidifying endolysosomal pH via a mucolipin transient receptor potential channel 1 (TRPML1) agonist provides protection against saquinavir- and darunavir-induced inhibition of oligodendrocyte maturation. Moreover, our findings suggest, for the first time, an imperative role of proper endolysosomal pH in regulating OL differentation, and that therapeutic targeting of endolysosomes may provide protection against ARV-induced oligodendrocyte dysregulation.
KeywordsAntiretroviral therapy Oligodendrocyte White matter Endolysosome
We thank the NIH AIDS reagent program for their generous donation of ARVs and the laboratory of Michael Robinson at The Children’s Hospital of Philadelphia for the use of the Odyssey Infrared Imaging System.
This project was supported by the following grants: RO1 MH098742 (KJS and JBG), R21 MH118121 (JBG and KJS), NIH F31 NS079192 (BKJ), T32 NS007180 (BKJ,), T32 GM008076 (LMR), P30GM100329, U54GM115458, R01MH100972, R01MH105329, 2R01NS065957 and 2R01DA032444 (JDG) and the Cellular Neuroscience Core of the Institutional Intellectual and Developmental Disabilities Research Core of the Children’s Hospital of Philadelphia (HD26979).
Compliance with Ethical Standards
Conflict of Interest
The authors declare no competing financial interests.
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