# HIV Tat and morphine-mediated pyroptosis activates astrocytes: Role of NLRP6 inflammasome in HAND

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2021 · $382,500

## Abstract

Project Summary
Despite the ability of combination antiretroviral therapy to dramatically suppress viremia, the brain continues to
be a reservoir of HIV low-level replication. Adding further complexity to this is the co-morbidity of drug abuse with
HIV-associated neurocognitive disorders and neuroHIV. Among several abused drugs, the use of opiates is
highly prevalent in HIV-infected individuals, both as an abused drug as well as for pain management. It has been
shown that both HIV/HIV proteins and abused drugs such as morphine contribute to neuroinflammation, which,
in turn, involves activation of the inflammasomes. Mounting evidence has also shown that noncoding RNAs
function as epigenetic and post-transcriptional regulators controlling vital cellular functions, including activation,
thus altering the dynamics of various biological processes. While both HIV proteins and opioids have been shown
to change the gene expression profiles of CNS cells, there is a gap of knowledge on the detailed molecular
mechanism(s) underlying the co-operative effects of HIV Transactivator of transcription (Tat) protein and
morphine on astrocyte activation. The central hypothesis of this proposal is that HIV Tat and morphine, via
distinct regulatory mechanism(s) augment astrocyte activation leading, in turn, to exacerbated
neuroinflammation. Our preliminary data on whole-genome bisulfite sequencing in the frontal cortices of SIV-
infected rhesus macaques show increased DNA hypomethylation of the NLRP6 (NOD-like receptor family, pyrin
domain-containing protein 6) promoter with a concomitant upregulation in NLRP6 expression. Additionally,
exposure of human and mouse primary astrocytes to HIV Tat and morphine also resulted in decreased
expression of microRNA-152 that was accompanied by increased expression of NLRP6. Interestingly, we also
found that exposure of these primary astrocytes to either HIV Tat or morphine resulted in increased cellular
activation with increased expression of proinflammatory cytokines (IL1β and IL18) via pyroptosis. Based on the
central hypothesis and the reliable preliminary data, this proposal led to the following specific aims: Specific Aim
1: Determine the molecular mechanism(s) involved in microRNA-152 mediated NLRP6 inflammasome activation
in HIV Tat and morphine-exposed astrocytes in vitro; Specific Aim 2: Determine the epigenetic mechanism(s)
involved in promoter DNA hypomethylation of the NLRP6 in HIV Tat and morphine-exposed astrocytes in vitro;
Specific Aim 3: Validate the combinatorial effects of HIV Tat and morphine on NLRP6 inflammasome mediated
astrocyte activation, in vivo. Understanding the mechanisms responsible for astrocyte activation induced by HIV
and morphine will set the stage for the future development of novel therapeutics aimed at dampening HIV and
opiate-mediated neuroinflammatory responses.

## Key facts

- **NIH application ID:** 10217093
- **Project number:** 5R01DA052266-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Palsamy Periyasamy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,500
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217093

## Citation

> US National Institutes of Health, RePORTER application 10217093, HIV Tat and morphine-mediated pyroptosis activates astrocytes: Role of NLRP6 inflammasome in HAND (5R01DA052266-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10217093. Licensed CC0.

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