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Cannabinoid modulation of EV composition and function in HIV/SIV infection

Award Number: R01DA050169
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Cannabinoid modulation of EV composition and function in HIV/SIV infection - Abstract Extracellular vesicles (EVs) are cargo carrying, quasi-nanovesicles that mediate intercellular communication. EVs are released by many cell types and are present in body fluids. The composition and function of EVs mirror that of the producing environment. Thus, EVs are implicated in regulating microbial pathogenesis, extracellular matrix reorganization, epithelial barrier dysfunction, and inflammatory cell recruitment. Indeed, we and others have shown that exosomes from body fluids, such as vaginal fluid and semen possess anti-HIV activity, and that use of drugs of abuse reprograms exosome phenotype and function. The goal of this multi-PI proposal is to leverage our expertise and resources to evaluate how cannabinoid (delta-9-tetrahydrocannabinol, THC) modulates the composition and function of EVs during HIV/SIV infection, focusing on the gastrointestinal tract (GI) and peripheral lymph nodes using the SIV-rhesus macaque model. HIV-infected (HIV+) patients are often comorbid with drug abuse and cannabis (marijuana) is one of the most commonly used drugs of abuse in the setting of HIV comorbidity. Approximately, 15–40% of HIV/AIDS patients use cannabis to treat disease symptoms and ameliorate side effects due to combinatorial antiretroviral therapy (cART). Recent research findings indicate that administration of THC―the most psychoactive anti-inflammatory cannabinoid in cannabis is linked to beneficial reduction in systemic inflammation and immune activation in cART-treated HIV+ patients. In the SIV/macaque model, THC ameliorated SIV disease progression, reduced intestinal T cell activation/exhaustion and prevented lymph node fibrosis. The benefits of THC is systemic―affecting many organs, including the GI and lymphoid systems. Gap in knowledge - The underlying mechanisms of THC- mediated reduction in systemic inflammation, immune activation, and lymph node fibrosis in HIV/SIV infection is unclear. Since 30 U.S. states allow the use of cannabinoids for medical purposes, with citations of HIV/AIDS as a condition amenable to such treatment; it is important to understand how THC regulates inflammation and disease progression in this population. Our preliminary data show that SIV infection results in a time-dependent increase in the release of proinflammatory EVs (VEH/SIV EV) that promote expression of inflammatory markers and cytoskeletal remodeling in monocytes and T cells. In contrast, chronic treatment with THC results in secretion of THC/SIV-EV that are lower in number, carry anti-inflammatory molecules, and counteracts VEH/SIV EV- induced cytoskeletal remodeling. Based on our published studies and these pilot data, our overarching hypotheses are that SIV infection of rhesus macaques (RMs) results in the shedding of VEH/SIV EV containing pro-inflammatory and pro-fibrogenic factors that promote chronic inflammation, epithelial barrier dysfunction, microbial translocation, and lymphoid fibrosis. Furthermore, chronic THC treatment in the setting of cART may reduce inflammation, microbial dysbiosis, lymphoid fibrosis, and restore immune function by modulating EV secretion and their cargo.


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: 2025 ( Subtotal = $0 )
2025	2023	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Drug Use and Addiction Research Programs	001	5	9/24/2025	NON-COMPETING CONTINUATION	$0
2025	2023	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Drug Use and Addiction Research Programs	000	5	10/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Drug Use and Addiction Research Programs	002	4	1/29/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,255,814
2024	2021	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	3	1/29/2024	NON-COMPETING CONTINUATION	-$745,173
2024	2020	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	2	1/29/2024	NON-COMPETING CONTINUATION	-$510,641
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $784,694 )
2023	2023	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Drug Use and Addiction Research Programs	001	5	7/17/2023	NON-COMPETING CONTINUATION	$784,694
2023	2022	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Drug Use and Addiction Research Programs	000	4	2/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $784,694

Issue Date FY: 2022 ( Subtotal = $775,988 )
2022	2022	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Drug Use and Addiction Research Programs	001	4	8/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$775,988
2022	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	3	8/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $775,988

Issue Date FY: 2021 ( Subtotal = $745,173 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	3	7/16/2021	NON-COMPETING CONTINUATION	$745,173
														Subtotal = $745,173

Issue Date FY: 2020 ( Subtotal = $787,400 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	002	2	7/20/2020	NON-COMPETING CONTINUATION	$787,400
2020	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	001	1	1/9/2020	NEW	$0
2020	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	1	11/19/2019	NEW	$0
														Subtotal = $787,400

Issue Date FY: 2019 ( Subtotal = $728,439 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Drug Use and Addiction Research Programs	000	1	9/17/2019	NEW	$728,439
														Subtotal = $728,439

Grand Total All Awards = $3,821,694

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Cannabinoid modulation of EV composition and function in HIV/SIV infection

Award Number: R01DA050169

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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