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Monocytic and exosomal cytochrome P450s in smoking-mediated HIV-1 pathogenesis

Award Number: R01DA047178
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Monocytic and exosomal cytochrome P450s in smoking-mediated HIV-1 pathogenesis - Despite the success of antiretroviral therapy (ART), effective treatment outcomes among people with HIV-1 occur in only 1/3rd of the total HIV-1-population who receives treatment. In addition to reduced adherence to ART treatment, consumption of substance of abuse including tobacco smoking, which is highly prevalent in people with HIV-1, is one of the major factors for ineffective treatment outcomes. Smoking is known to exacerbate HIV- 1 pathogenesis in monocytes and macrophages, which serve as sanctuary sites for HIV-1 and infiltrate the brain, spreading the virus to perivascular macrophages and microglia and causing development of neuroAIDS. It is difficult to eliminate the virus in macrophages by ART. In addition, smoking accelerates HIV-1 replication, in part via increased oxidative stress. Our objective is to determine the role of monocytic and plasma exosomal CYP enzymes in enhancing smoking-mediated HIV-1 replication in smokers. We will accomplish our objective by testing the hypotheses that: 1) monocytic CYP enzymes mediate enhanced HIV-1 replication in smokers by contributing to increased oxidative stress and decreased ART efficacy and 2) circulating plasma exosomal CYP enzymes, secreted from liver and lung cells, are induced in smokers and delivered to macrophages contributing to enhanced HIV-1 replication. The rationale for the hypothesis is based on literature reports that smoking exacerbates HIV-1 replication in macrophages. Our own studies suggest that CYP enzymes are induced by tobacco smoking in monocytes and perhaps in plasma exosomes, and play a critical role in oxidative stress and ART metabolism in macrophages. We plan to test the hypotheses by determining the: Aim 1: Contribution of monocytic CYP enzymes in tobacco-enhanced HIV-1 replication in macrophages; Aim 2: Ex vivo validation of the role of CYP enzymes in smoking-enhanced HIV-1 replication; Aim 3: Contribution of plasma exosomal CYP enzymes to HIV-1 replication in macrophages. Upon completion of this project, we expect to determine the mechanistic contributions and gain a new understanding of a novel role of monocytic and plasma exosomal CYP enzymes in smoking-mediated HIV-1 pathogenesis. Thus, the project would impact the treatment of HIV-1 who smoke by providing a new target for novel therapeutic interventions, and potential application of exosomes as therapeutic carriers in effectively treating these patients.


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 = -$2,475 )
2025	2022	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	001	5	12/6/2024	NON-COMPETING CONTINUATION	-$25
2025	2022	UNIVERSITY OF TENNESSEE	62 S DUNLAP ST	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	5	11/13/2024	NON-COMPETING CONTINUATION	-$2,450
														Subtotal = -$2,475

Issue Date FY: 2022 ( Subtotal = $342,000 )
2022	2022	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	5	6/29/2022	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2021 ( Subtotal = $342,000 )
2021	2021	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	4	6/28/2021	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2020 ( Subtotal = $342,000 )
2020	2020	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	3	6/26/2020	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2019 ( Subtotal = $342,000 )
2019	2019	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	2	7/1/2019	NON-COMPETING CONTINUATION	$342,000
														Subtotal = $342,000

Issue Date FY: 2018 ( Subtotal = $342,000 )
2018	2018	UNIVERSITY OF TENNESSEE	62 S DUNLAP STREET STE 103	MEMPHIS	TN	38103	SHELBY	USA	Drug Use and Addiction Research Programs	000	1	9/14/2018	NEW	$342,000
														Subtotal = $342,000

Grand Total All Awards = $1,707,525

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Monocytic and exosomal cytochrome P450s in smoking-mediated HIV-1 pathogenesis

Award Number: R01DA047178

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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