Acidic nanoparticles prevent HIV pre-exposure prophylaxis (PrEP)-induced oligodendrocyte impairments by restoring lysosomal pH in adolescents

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Neuroscience
Discipline
Neuroscience and Neurobiology
Subject
HIV
Lysosome
Oligodendrocyte
PrEP
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2024
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Author
Long, Caela
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Abstract

Each year, 13- to 24-year-olds disproportionately compose the number of individuals diagnosed with human immunodeficiency virus (HIV) in the United States. Even with effective peripheral viral suppression by antiretroviral therapy (ART), this population is at risk for significant life-long behavioral, cognitive, and motor impairments as approximately 30-50% of people with HIV (PWH) develop HIV-associated neurocognitive disorders (HAND). White matter abnormalities are a hallmark of HAND and transcriptome analysis have found a significant decrease in the expression of genes associated with oligodendrocytes and the myelin sheath they synthesize in the white matter of ART treated PWH. Our lab has demonstrated that even in the absence of HIV, select antiretroviral drugs of the integrase inhibitor (INSTI) and protease inhibitor (PI) classes inhibit oligodendrocyte differentiation in vitro. PrEP, a combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) of the NRTI antiretroviral class, is an effective method to prevent the transmission of HIV in adolescents at substantial risk for acquiring HIV. However, as myelination continues through adolescence and into adulthood, it is important to understand the effect of PrEP on developing white matter, which has not been investigated. Here, we report that PrEP significantly reduced oligodendrocyte maturation in adolescent rats. Furthermore, cultures of primary rat oligodendrocyte progenitors treated with PrEP showed inhibited oligodendrocyte differentiation through deacidification of lysosomes resulting in lysosomal accumulation of myelin proteins. Acidic nanoparticle co-administration with PrEP prevented PrEP-induced oligodendrocyte maturation impairments both in vivo and in vitro. These studies suggest uninfected adolescents are vulnerable to PrEP-induced oligodendrocyte impairments and identify maintenance of lysosome pH as a critical factor in antiretroviral design.

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Grinspan, Judith
Jordan-Sciutto, Kelly
Date of degree
2024
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