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Neuroimmune pathways linking chronic psychosocial stress to co-occurring stimulant use and depression in HIV disease: a mechanistic clinical trial

Award Number: R01DA061952
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Neuroimmune pathways linking chronic psychosocial stress to co-occurring stimulant use and depression in HIV disease: a mechanistic clinical trial - People with HIV (PWH) who use stimulants experience profound intersectional stigma and discrimination that can cause considerable psychosocial stress. An overactive, unresolved stress response fuels systemic inflammation, which may be a common pathway linking psychosocial stressors to complex neuropathology in HIV. Chronic stress can disrupt central nervous system functions that regulate reward processing. Our team and others have shown that these pathophysiologic alterations are amplified by stimulant use and potentiate neuropsychiatric symptoms. However, the inflammatory mechanisms through which stress affects brain networks that subserve substance use and psychiatric multi-morbidity in HIV remain unknown. The overarching goal of this proposal is to identify neuroimmune mechanisms that underlie the intersection of social stigma, anhedonia, and altered reward processing in PWH who use stimulants (e.g., cocaine, methamphetamine). Embracing the experimental rigor of a randomized controlled trial (RCT) design, we will leverage an evidence-based positive affect intervention (ARTEMIS) as a mechanistic probe to elucidate the neural and immunologic substrates linking psychosocial stress to substance use and depression in PWH. With this translational approach, we aim to: (1) Investigate the causal link between ARTEMIS-induced improvements in anhedonia and neural functioning in reward circuitry using resting-state and task-based functional MRI; (2) Evaluate the effects of ARTEMIS on transcriptional control pathways and downstream markers of peripheral inflammation; and (3) Test whether reductions in proinflammatory markers have positive feedback on reward functioning and stimulant use. To achieve these specific aims, we will enroll 189 PWH who currently use stimulants and have suppressed HIV viral load. Participants will be randomly assigned on a 2:1 ratio to receive ARTEMIS or a wait-list control. To support durable HIV viral suppression throughout the trial, all participants will receive smartphone-based contingency management for ART adherence. Assessments at 3- and 6-month follow-ups will characterize changes in neural functioning and leukocyte signaling as plausible mediators of ARTEMIS effects on behavioral outcomes. Our innovative and clinically important proposal is highly responsive to RFA-DA-24-005 and will advance our basic understanding of the neuroimmune pathways underlying psychological resilience to social stress that may mitigate substance use and depression in PWH. This proposal provides a scientifically rigorous model for examining the causal associations amongst these prevalent comorbidities in a population that is critical to ending the HIV epidemic, while also providing participants with the benefit of an evidence-based intervention with a transdiagnostic target. The results of this mechanistic trial will identify preclinical targets for novel pharmacotherapies linked to reward circuitry.


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 = $1,096,685 )
2026	2026	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	3	6/12/2026	NON-COMPETING CONTINUATION	$1,096,685
														Subtotal = $1,096,685

Issue Date FY: 2025 ( Subtotal = $1,201,542 )
2025	2025	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	001	2	5/8/2025	NON-COMPETING CONTINUATION	$1,201,542
2025	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	1	4/21/2025	NEW	$0
														Subtotal = $1,201,542

Issue Date FY: 2024 ( Subtotal = $869,488 )
2024	2024	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Drug Use and Addiction Research Programs	000	1	8/30/2024	NEW	$869,488
														Subtotal = $869,488

Grand Total All Awards = $3,167,715

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Neuroimmune pathways linking chronic psychosocial stress to co-occurring stimulant use and depression in HIV disease: a mechanistic clinical trial

Award Number: R01DA061952

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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