# Targeting autophagy to reduce inflammasome-mediated inflammation and immune dysfunction in HIV and methamphetamine use

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $707,947

## Abstract

Project Summary/Abstract
 Methamphetamine (MA), a potent addictive psychostimulant, is highly prevalent in HIV-infected
individuals. Even for individuals with suppressive anti-retroviral therapy (ART), MA abuse has been linked to
increased viral load, accelerated disease progression, and higher mortality rates in people living with HIV
(PLWH). Despite well-documented evidence of MA's adverse effects on the central nervous system (CNS) and
cognitive function, its effects on immunity remain unclear. Further research is needed to determine the
molecular mechanisms of MA on the immune system, which could lead to targeted therapeutic interventions.
Previous reports and our studies showed that MA could impair mitochondria function and exacerbate
inflammasome activation and chronic inflammation during HIV infection. Autophagy, a homeostatic cellular
mechanism involved in disposal of damaged organelles and intracellularly pathogens, has been reported to
negatively regulate inflammasome activation. Our recent studies indicate that autophagy inducers such as
rapamycin can induce autophagy, improve mitochondria function, reduce inflammasome activation and chronic
inflammation in HIV infected humanized mice. We also observed improved anti-viral T cell immunity, reduced
viral reservoir and lower viral rebound after ART withdrawal in rapamycin treated mice, suggesting its
therapeutic potentials. In addition, we found that cannabis major components trans-Δ9-tetrahydrocannabinol
(THC) and cannabidiol(CBD) can potently induce autophagy and reduce inflammasome activation in stimulated
macrophages. Therefore, we hypothesize that inducing autophagy through rapamycin or THC/CBD may offer
therapeutic benefits in reducing inflammasome-mediated inflammation in both the periphery and CNS in
individuals with HIV infection and MA use. This, in turn, could enhance anti-viral immunity and decrease viral
reservoirs. We will study the following aims: 1) Determine the effects of methamphetamine on inflammasome
activation and T cell dysfunction during HIV infection with or without ART; 2) Examine the therapeutic potential
of targeting autophagy to reduce excessive inflammasome activation and restore T cell function during HIV
infection and methamphetamine abuse; 3) Investigate the effects of MA and autophagy induction on HIV-
associated CNS inflammation.

## Key facts

- **NIH application ID:** 10811321
- **Project number:** 1R01DA059873-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Jennifer Fulcher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $707,947
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811321

## Citation

> US National Institutes of Health, RePORTER application 10811321, Targeting autophagy to reduce inflammasome-mediated inflammation and immune dysfunction in HIV and methamphetamine use (1R01DA059873-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10811321. Licensed CC0.

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