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

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2024 · $36,413

## Abstract

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.

## Key facts

- **NIH application ID:** 10846727
- **Project number:** 5F31MH128135-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Caela Long
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,413
- **Award type:** 5
- **Project period:** 2022-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846727

## Citation

> US National Institutes of Health, RePORTER application 10846727, Pre-Exposure Prophylaxis (PrEP) inhibits oligodendrocyte differentiation in vivo (5F31MH128135-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10846727. Licensed CC0.

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