Thursday, June 5, 2025 6/5/2025

Single cell brain transcriptome changes during chronic HIV infection and opiate use in conventional mice

Award Number: U01DA053629
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Single cell brain transcriptome changes during chronic HIV infection and opiate use in conventional mice - PROJECT SUMMARY This application is submitted in response to RFA-D-21-019: Single Cell Opioid Responses in the Context of HIV (SCORCH) Program Expansion: CNS Data Generation for Chronic Opioid, Methamphetamine, and/or Cocaine Exposures. Human immunodeficiency virus (HIV) can infect nonneuronal cells in the brain, particularly microglia, with these cells acting as a reservoir of latent infection. HIV infection has deletions effects on the function of nonneuronal and neuronal cells, including those cells located in brain sites relevant to cognition, emotion and motivation. The same brain sites impacted by HIV are known to regulate the actions of opioids and other classes of addictive drugs, and opioid use disorder (OUD) is more prevalent in HIV-infected individuals than the general population. Moreover, HIV infection and OUD reciprocally interact, with each condition potentially exacerbating the severity of the other. Mice infected with EcoHIV, a modified HIV strain that targets CD4+ T cells, macrophages and microglia, recapitulates the major pathobiological features of chronic HIV infection in individuals on antiretroviral therapy (ART). Here, we will leverage state-of-the-art single cell sequencing (scSeq), molecular, cellular and behavioral approaches to define cell type-specific interactions between HIV and opioids in the brains of EcoHIV-infected mice. In Specific Aim I, we optimize the intravenous (IV) heroin self-administration procedure, already well-established in our laboratories, for use in EcoHIV- infected mice. We will then examine the effects of EcoHIV infection on the expression of opioid addiction-relevant behaviors. Conversely, we will examine the effects of heroin consumption on the expression of cognitive abnormalities in EcoHIV-infected mice relevant to HIV-associated neurocognitive impairment (HIV-NCI) in humans. Finally, will examine the effects of ART on the expression of addiction- and HIV-NCI-relevant behavioral abnormalities in EcoHIV-infected mice. In Specific Aim II, we will perform scSeq on brain regions relevant to opioid addiction and HIV-NCI, collected from EcoHIV mice with our without a history of intravenous opioid self- administration behavior. We will investigate the effects of ART on scSeq patterns in these mice. The scSeq data will be mined to identify cells in the brain infected by EcoHIV, and determine which cells show the most robust transcriptional responses to EcoHIV in opioid-naïve and opioid-experienced mice. In situ hybridization and immunohistochemistry will be used to validate key findings and prioritize candidate genes for further investigation. In Specific Aim III, we will use in vivo CRISPR-Cas9 to target prioritized genes identified in Aim II in a cell type- and brain region-specific manner. The impact of CRISPR cleavage of prioritized genes on the expression of addiction- and HIV-NCI-relevant behavioral abnormalities in EcoHIV-infected mice will be examined. This innovative program of research may yield fundamental new insights into disease-relevant interactions between HIV infection and opioid drugs.


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 = $1,641,558 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	5	2/26/2025	NON-COMPETING CONTINUATION	$1,477,403
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	001	5	4/8/2025	NON-COMPETING CONTINUATION	$164,155
														Subtotal = $1,641,558

Issue Date FY: 2024 ( Subtotal = $1,641,558 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	001	4	4/29/2024	NON-COMPETING CONTINUATION	$164,155
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	4	2/1/2024	NON-COMPETING CONTINUATION	$1,477,403
														Subtotal = $1,641,558

Issue Date FY: 2023 ( Subtotal = $2,506,585 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	3	6/26/2023	NON-COMPETING CONTINUATION	$2,506,585
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	001	3	9/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,506,585

Issue Date FY: 2022 ( Subtotal = $2,641,224 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	2	3/18/2022	NON-COMPETING CONTINUATION	$2,641,224
														Subtotal = $2,641,224

Issue Date FY: 2021 ( Subtotal = $2,654,681 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	001	1	5/18/2021	NEW	$0
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Drug Use and Addiction Research Programs	000	1	5/14/2021	NEW	$2,654,681
														Subtotal = $2,654,681

Grand Total All Awards = $11,085,606

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Single cell brain transcriptome changes during chronic HIV infection and opiate use in conventional mice

Award Number: U01DA053629

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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