# Reversal of HIV latency by METH and Inflammation

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $721,059

## Abstract

Summary
One in three HIV-infected individuals develops some form of HIV-associated neurocognitive
disorder (HAND). Consumption of drugs of abuse such as methamphetamine (METH) aggravates
the symptoms of HAND, but the cellular and molecular mechanisms by which these drugs impact
HIV disease progression in the central nervous system (CNS) remain ill-defined. In this study we
will thoroughly test the hypothesis that HAND is the result of the neurotoxic effects of HIV proteins
synthesized when latently infected microglial cells respond to signs of neurodegeneration. We will
also test the hypothesis that exposure to drugs of abuse enhance HIV replication and exacerbate
HAND. This highly multidisciplinary investigation is a close collaboration between the laboratories
of Dr. Jonathan Karn (CWRU), an expert in the molecular mechanisms HIV latency, and Dr. Kurt
Hauser, a neurobiologist and expert on drug abuse (VCU). We have recently established a
reliable and robust method to develop immortalized microglial cells from primary glia derived from
fresh CNS tissue, and used them to create microglia/HIV cellular models. The proposal capitalizes
on findings of an unbiased shRNA library screen, which revealed that the Nurr1/CoREST trans-
repressor complex plays a key role in silencing HIV in microglial cells, a mechanism which is
distinct from silencing in memory T-cells. Building on these observations, we will study the
epigenetic machinery leading to silencing of the HIV promoter, including Nurr1/CoREST, by
chromatin immunoprecipitation experiments (Chip-Seq), and study the impact of both acute and
chronic treatment with METH on reversing HIV latency. Our experiments will also uncover the
inflammatory signals that, together with METH, induce HIV expression. Finally, using two novel
co-culture systems, we will demonstrate how METH-primed microglia/HIV cells exacerbate
neuronal damage. Successful completion of these studies will provide a detailed understanding
of fundamental biology of HIV-infected microglia in response to METH. By establishing the
relationship between HIV latency, inflammation, and neuronal damage we will provide new
insights into the development of HAND in HIV patients and how this is augmented by METH
abuse.

## Key facts

- **NIH application ID:** 9963178
- **Project number:** 5R01DA043159-05
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** JONATHAN KARN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $721,059
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963178

## Citation

> US National Institutes of Health, RePORTER application 9963178, Reversal of HIV latency by METH and Inflammation (5R01DA043159-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9963178. Licensed CC0.

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