Pre-Exposure Prophylaxis (PrEP) inhibits oligodendrocyte differentiation in vivo

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PROJECT SUMMARY: Each year 13- to 24-year-olds disproportionately compose the number individuals diagnosed with human immunodeficiency virus (HIV) in the United States. Preexposure prophylaxis (PrEP), a once daily antiretroviral regime, is an effective method to prevent the transmission of HIV in adolescents at substantial risk for acquiring HIV, however, the effect of this regimen on the development of critical brain structures during adolescence is unknown. Adolescents taking PrEP are uniquely vulnerable to myelin impairments as the adolescent brain is undergoing high rates of myelination. Our lab has shown that primary oligodendrocyte precursor cell cultures treated with therapeutic concentrations of select antiretroviral drugs displayed dose-dependent decreases in oligodendrocyte maturation. A gap in our knowledge is the mechanistic basis of the inhibition of oligodendrocyte maturation by antiretrovirals in an HIV-negative, adolescent population. My preliminary data suggests that emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), the drugs composing PrEP, de-acidify oligodendrocyte lysosomes. Furthermore, my preliminary data also suggests that PrEP decreases SREBP2 expression in oligodendrocytes in vitro. mTORC1 regulates lipogenesis through the transcription factors SREBP 1 and 2, with the latter regulating the expression of genes involved in cholesterol synthesis, the rate-limiting step of myelination. Lysosome de-acidification has been shown to result in increased mTORC1 signaling in osteoclasts but remains to be investigated in oligodendrocytes. Additionally, overactivation of mTORC1 in oligodendrocytes is known to result in hypomyelination and decreased SREBP2 expression. Taken together, I hypothesize that oligodendrocyte maturation is inhibited by PrEP through lysosome deacidification resulting in increased mTORC1 activation and decreased lipogenesis. I will address this hypothesis in the following specific aims. In Aim 1 I will demonstrate oligodendrocyte maturation is impaired by PrEP through lysosome de- acidification in vitro. In Aim 2, I will demonstrate that PrEP inhibits oligodendrocyte maturation through increased mTORC1 signaling and subsequent decreased lipogenesis in vitro. In Aim 3, I will demonstrate that oligodendrocyte maturation and myelination are impaired by PrEP and lysosome acidification rescues myelination in vivo. Overall, these experiments will investigate the previously unanswered question of whether PrEP affects oligodendrocyte maturation in HIV- negative individuals.