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Contribution of Neuronal Mitochondrial Dysfunction and Microglial HIV Reservoirs to Neurocognitive Aging in African Americans with Nicotine Addiction and Viral Suppression.

Award Number: R21DA064859
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2026
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Contribution of Neuronal Mitochondrial Dysfunction and Microglial HIV Reservoirs to Neurocognitive Aging in African Americans with Nicotine Addiction and Viral Suppression. - Project Summary/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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $400,125 )
2026	2026	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Drug Use and Addiction Research Programs	000	1	3/10/2026	NEW	$400,125
														Subtotal = $400,125

Grand Total All Awards = $400,125

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Contribution of Neuronal Mitochondrial Dysfunction and Microglial HIV Reservoirs to Neurocognitive Aging in African Americans with Nicotine Addiction and Viral Suppression.

Award Number: R21DA064859

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/15/2026

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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