# HIV opiate interactions in white matter pathology

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $580,492

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Hauser, Kurt F. & Knapp, Pamela E.
HIV-associated neurocognitive disorder (HAND) remains a serious clinical problem even in patients receiving
cART, and HIV-infected persons who abuse opiates are at greater risk for HAND. Opiates can act directly via
µ-opiate receptors (MOR) on glia to amplify secondary neurotoxic effects. The concept that damage to
oligodendroglia (OLs) adds to neurologic deficits in HIV is largely unexplored, even though white matter deficits
occur quite early after infection. Importantly, our experimental work shows that OLs are vulnerable to viral
protein or HIV exposure. A 7 d co-exposure of transgenic mice to HIV-1 Tat ± morphine damages OLs, which
exhibit cytoarchitectural/ultrastructural anomalies, and elevated caspase-3 and TUNEL expression, the latter
indicating OL death (69; Fig 1). OLs are the only CNS cell type that die in situ in response to acute Tat and
morphine coexposure. In vitro, Tat kills developing OLs, while mature OLs instead show a loss of myelin
membrane; both outcomes are related to Ca2+- and GluR-mediated mechanisms (84). OL damage, in addition
to vascular/blood brain barrier damage, would contribute to myelin pallor consistently noted in imaging studies.
Our central hypothesis is that HIV-1 Tat interacts with opiates to directly injure MOR-expressing OLs.
Since immature OLs express MOR and are preferentially vulnerable to HIV/Tat, we predict that myelin repair
processes are especially vulnerable. Herein, we propose a comprehensive morphological and functional
assessment of the time course of OL and myelin damage caused by acute and chronic (≤3 month) HIV/Tat and
morphine coexposure. Opiate exposure is intermittent to better model the exposure of injection drug users
(IDUs) who contract HIV. Studies are done in both sexes, as myelination is influenced by sex steroids. The
central hypothesis is tested in 3 related aims. Aim 1 develops a thorough picture of opiate-related OL and
myelin damage in situ using an HIV-1 Tat model. Function is assessed using electrophysiology; damage to
white matter tracts and OLs is assessed by histology, high resolution DT-MRI and tractography/connectivity,
stereology, and electron microscopy. Vascular changes as assessed by blood-brain barrier leakiness are
monitored histologically and correlated with areas of demyelination. In Aim 2, MOR is deleted from OLs to test
whether opiate interactions occur via direct actions on OLs in vivo; the direct effects of morphine ± HIV, Tat
and gp120 on MOR-expressing, human OLs are compared in vitro. Aim 3 tests structural and functional
recovery after morphine is withdrawn. These comprehensive studies answer critical questions about OL/myelin
vulnerability and the potential for their recovery after combined HIV/Tat and opiate insults.
OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page

## Key facts

- **NIH application ID:** 9952325
- **Project number:** 5R01DA044939-04
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Kurt F Hauser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $580,492
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952325

## Citation

> US National Institutes of Health, RePORTER application 9952325, HIV opiate interactions in white matter pathology (5R01DA044939-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9952325. Licensed CC0.

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