Contribution of neuronal mitochondrial dysfunction and microglial HIV reservoirs to neurocognitive aging in african americans with nicotine addiction and viral suppression

The National Institute on Drug Abuse awarded Meharry Medical College $400,125 on March 15, 2026, under the Drug Use and Addiction Research Programs (CFDA 93.279) to investigate neuronal mitochondrial dysfunction and microglial HIV reservoirs in African Americans with nicotine addiction and viral suppression.

The research addresses accelerated neurocognitive aging in African Americans living with HIV despite effective antiretroviral therapy. The project examines how persistent microglial HIV reservoirs, exacerbated by nicotine exposure, disrupt neuronal mitochondria and accelerate cognitive decline. Smoking increases oxidative stress and inflammation, compounding mitochondrial dysfunction and neuroinflammation, leading to greater neuronal injury. The study proposes two specific aims: quantifying mitochondrial DNA in neuron-derived extracellular vesicles from blood plasma to assess neuronal mitochondrial dysfunction and its link to neurocognitive impairment, and measuring HIV RNA in microglia-derived extracellular vesicles from blood plasma to assess microglial reservoir activity and its contribution to neurocognitive aging. The project's long-term goal is to mitigate HIV-associated neurocognitive disorders by targeting neuronal mitochondrial dysfunction and persistent microglial HIV reservoirs, particularly in African Americans with nicotine addiction.

Performance occurs in Nashville, Tennessee. The award period runs from March 15, 2026, through February 29, 2028. This is a Project Grant, the assistance type under NIDA's substance use and addiction research program supporting basic, clinical, translational, and implementation research for prevention, diagnosis, and treatment of drug use, misuse, and addiction, and related health outcomes including HIV/AIDS.

Abstract

African americans living with HIV experience accelerated neurocognitive aging despite effective antiretroviral therapy (art). This project, contribution of neuronal mitochondrial dysfunction and microglial HIV reservoirs to neurocognitive aging in african americans with nicotine addiction and viral suppression, investigates how persistent microglial HIV reservoirs, exacerbated by nicotine exposure, disrupt neuronal mitochondria and accelerate cognitive decline. Smoking increases oxidative stress and inflammation, compounding mitochondrial dysfunction and neuroinflammation, leading to greater neuronal injury. Microglia sustain these pathological processes despite systemic viral suppression, contributing to HIV-associated neurocognitive disorders (HAND). Our long-term goal is to mitigate HAND by targeting the core drivers of neurocognitive decline-neuronal mitochondrial dysfunction and persistent microglial HIV reservoirs-particularly in african americans with nicotine addiction. We hypothesize that chronic microglial HIV reservoir activity accelerates neuronal mitochondrial dysfunction and that nicotine amplifies these effects, leading to earlier and more severe neurocognitive deficits. To test this hypothesis, we propose the following specific aims: aim 1: quantify mitochondrial DNA (MTDNA) in neuron-derived extracellular vesicles (NEVS) from blood plasma to assess neuronal mitochondrial dysfunction and its link to neurocognitive impairment in african americans with nicotine addiction and viral suppression. Aim 2: measure HIV RNA in microglia-derived extracellular vesicles (MEVS) from blood plasma to assess microglial reservoir activity and its contribution to neurocognitive aging in african americans with nicotine addiction and viral suppression. We will recruit african american participants stratified by HIV status, smoking behavior, age, and SEX. NEVS and MEVS will be isolated from blood plasma using neuron- and microglia-specific antibodies. Biomarkers- MTDNA (neuronal mitochondrial dysfunction) and HIV RNA (microglial reservoirs)-will be quantified using droplet digital PCR (DDPCR) for MTDNA and reverse transcription-DDPCR (RT-DDPCR) for HIV RNA. Neurocognitive function will be assessed with standardized tests, and statistical analyses will correlate biomarker levels with demographic variables and cognitive outcomes. Our preliminary findings indicate increased MTDNA in NEVS and detectable HIV RNA in MEVS among african american men with HIV who smoke, supporting the study's hypothesis. By integrating biomarker assays with neurocognitive testing, this project will elucidate how microglial HIV reservoirs and nicotine disrupt neuronal mitochondrial integrity and contribute to cognitive decline. Findings will inform precision-medicine strategies to reduce HAND-related health disparities in african americans living with HIV and nicotine addiction.