# HIV Tat & cocaine-mediated alterations in microglial migration & activation involve epigenetic reulation of miRNAs

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $376,250

## Abstract

Abstract:
Drug abuse and HIV-1 are two linked global health crises. Despite the recognized impact of cocaine abuse on
the clinical course of HIV-1-associated neurological disorder (HAND), the mechanisms underlying the ability of
cocaine to modulate central nervous system (CNS) pathology remain elusive. Neuroinflammation involving
robust microglial activation has emerged as an important phenotype and correlate of HIV infection and drug
abuse despite the advent of combined anti-retroviral therapy (cART). The underlying cause of HIV-associated
neuroinflammation is likely attributable to the fact that following virus infection and formation of the proviral
DNA, cART is ineffective in abrogating the expression of toxic viral gene products such as Tat and gp120, that
continue to be present in tissues such as the CNS. Furthermore, similar to HIV positive subjects on cART, SIV-
infected rhesus macaques on cART also demonstrate increased glial activation, which was shown to be
associated with dysregulation of various signature microRNAs (miRs). Emerging evidence also points to the
role of drugs such as cocaine in mediating glial activation with global changes in miRs. In fact, in a recent
finding, we demonstrate that cocaine-mediated activation of microglia involves down-regulation of miR-124
expression both in vitro and in vivo. Furthermore, we have also elucidated that HIV Tat mediated microglial
migration involves upregulated expression of miR-9 with a concomitant downregulation of its target, monocyte
chemotactic protein-induced protein 1 (MCPIP1). We thus hypothesize that both cocaine and HIV Tat modulate
increased microglial activation and migration respectively, via two distinct mechanisms: a) cocaine mediates
downregulation of miR-124 via DNA methylation of its promoter, leading in turn, to increased TLR4 signaling
that culminates into increased microglial activation and, b) exposure of microglia to HIV Tat upregulates the
expression of miR-9 leading in turn, to enhanced microglial migration via downregulation of the target MCPIP1.
Three experienced PIs (Drs. Buch, Hu, & Guo) will co-lead this project to accomplish the proposed goals. This
proposal is responsive to the RFA (RFA-DA-16-012) focusing on epigenomic and non-coding RNA regulation
in HIV/AIDS and substance abuse.

## Key facts

- **NIH application ID:** 9944463
- **Project number:** 5R01DA043138-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Shilpa J Buch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $376,250
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944463

## Citation

> US National Institutes of Health, RePORTER application 9944463, HIV Tat & cocaine-mediated alterations in microglial migration & activation involve epigenetic reulation of miRNAs (5R01DA043138-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9944463. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*