Mitigating HIV-associated premature aging through cannabinoid-mediated anti-inflammatory mechanisms

The National Institute on Drug Abuse awarded Louisiana State University Health Sciences Center New Orleans $723,353 under the Drug Use and Addiction Research Programs (CFDA 93.279) on September 1, 2026.

The award funds research examining HIV-associated premature aging through cannabinoid-mediated anti-inflammatory mechanisms. The recipient's research team has established an autopsy program studying HIV viral tissue reservoirs and neuropathogenesis in deceased people living with HIV, analyzing 459 full-body autopsy cases including brain tissues. Preliminary findings indicate that HIV tissue reservoirs were significantly reduced in cases with cannabis use and correlated with decreased pro-inflammatory cytokines; DNA methylation epigenetic clock analyses also showed that people with HIV who used cannabis exhibited cell-type specific biological aging of neurons similar to uninfected individuals of comparable age, suggesting cannabis may slow neuronal aging through anti-inflammatory effects. The project expands this preliminary analysis to further determine the extent of brain cell-type specific biological aging and the role of cannabinoid-mediated mechanisms in mitigating premature aging.

Work is performed in New Orleans, Louisiana. The project period runs from September 1, 2026, through June 30, 2031. The assistance type is a Project Grant, supporting basic and translational research in substance use and related health outcomes including HIV/AIDS.

Abstract

The unaids in 2023 estimated that 8.1 out of 40 million people living with HIV (PWH) globally were 50 years or older, 41% of PWH in the U.S. Are at least 55 years old, and are at increased risk for chronic diseases such as cancer and premature aging. The extended lifespan, poor art penetration of the brain, neuroviral replication, and chronic neuroinflammation in PWH can all lead to early onset of age-related neurodegenerative diseases. Our team have established an autopsy program on deceased PWH to study HIV viral tissue reservoirs and neuropathogenesis. We have collected 459 deceased cases full-body autopsy tissues, including brain tissues to identify viral reservoirs and the effects of cannabis use on the size and distribution of the HIV tissue reservoir since chronic inflammation plays a role in sustaining the reservoirs, and cannabinoids have been shown to have anti-inflammatory effects. We found HIV tissue reservoirs were significantly reduced in cases with cannabis use, and correlates with a decrease in pro-inflammatory cytokines in the viral tissue reservoirs. Critically, our preliminary analysis on the whole brain tissues of PWH found an increase in cell-type specific biological aging of neurons in brains of PWH through DNA methylation epigenetic clock analyses, which paralleled the detection of neuropathology at a younger age in PWH as compared to uninfected individuals. Interestingly, our methylation analysis of various brain tissues also showed PWH who used cannabis have similar cell-type specific biological aging of neurons as uninfected group with similar age, suggesting that cannabis may slow-down aging in PWH possibly due to its anti-inflammatory effect. Therefore, our overall objective of the proposed study is to build onto our preliminary findings by expanding the analysis of autopsied tissues to determine the extent of brain cell-type specific premature aging in PWH, whether cannabis use mitigates such an effect and identify potential mechanisms involved. We hypothesize that HIV- induced chronic inflammation accelerates cell-type specific biological aging programs in PWH, and cannabis use can counteract the premature aging via its anti-inflammatory effects. Our aims are: 1) determine whether HIV infection enhances cell-type specific epigenetic age and gene expression profiles in the brain regions across the lifespan; 2) determine whether cannabis use is associated with reduced cell-type specific epigenetic age acceleration, and gene expression alterations across brain regions of PWH; 3) determine neuroimmune mechanisms linking HIV, epigenetic changes, inflammation, and evaluate the anti-inflammatory role of cannabis. This study will provide a detailed understanding of the spatial distribution of epigenetic changes across age groups in PWH, identify the underlying mechanisms of premature aging in the context of infection, and evaluate cannabis's effects in reducing premature aging due to HIV infections. Insights from this study will inform targeted interventions to mitigate brain aging in PWH in the U.S. And globally.