# Oligodendrocyte damage and dysfunction in HIV associated neurocognitive disorder

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $681,019

## Abstract

Despite effective viral control by Antiretroviral therapy (ART), HIV associated neurocognitive disorder (HAND)
persists in 30-50% of patients. In the ART era, neuropathology has shifted from a rapidly progressing
encephalitic condition to a prolonged neurodegenerative disease with pathologic features including
astrogliosis, microgliosis, dendritic damage, and especially white matter deficits. White matter alterations
include decreased myelin sheath thickness, myelin lesions, and abnormal myelin protein expression. The
severity of white matter damage correlates with the amount of time on ART therapy. Transcriptome analysis of
HIV patients on ART revealed decreases in genes associated with oligodendrocyte maturation and
myelination. Using a well-characterized oligodendrocyte culture model, we have recently reported that
representative drugs from the protease inhibitor class of ART (ritonavir and lopinavir) inhibit differentiation of
oligodendrocyte precursors to mature oligodendrocytes in a dose-dependent manner, independent of cell
death. Intravenous administration of ritonavir to mice for only two weeks significantly decreased the expression
of several myelin proteins. Further, myelin basic protein (MBP) was significantly decreased in the cortex of HIV
patients who were on ART and exhibited HAND. These findings are the first to demonstrate on an
experimental level that ART can disrupt myelin development and maintenance. We hypothesize that ART
compounds alter oligodendrocyte differentiation, function, and survival, contributing to the persistence of HAND
in the post-ART era. Our new preliminary data suggest that a subset of drugs from the nucleoside reverse
transcriptase inhibitor (NRTI) class and from the integrase inhibitor class also decrease oligodendrocyte
differentiation in vitro. In this proposal, we will use our oligodendrocyte cell culture system to identify
mechanisms by which ART drugs decrease oligodendrocyte maturation, including lipid regulation and cellular
stress pathways in oligodendrocytes, which regulate myelin membrane generation. The second aim of this
proposal will examine whether ART drugs can impede remyelination after a demyelinating insult using small
animal model of HIV-induced neuroinflammation and the cuprizone model of demyelination. The third aim will
compare white matter changes in our rodent model with human patients using image analysis. Results from
these aims should help devise more rational drug therapies without myelin deficits to reduce HAND.

## Key facts

- **NIH application ID:** 9842332
- **Project number:** 5R01MH098742-08
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** JUDITH B GRINSPAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $681,019
- **Award type:** 5
- **Project period:** 2012-07-16 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842332

## Citation

> US National Institutes of Health, RePORTER application 9842332, Oligodendrocyte damage and dysfunction in HIV associated neurocognitive disorder (5R01MH098742-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9842332. Licensed CC0.

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