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Uncovering Mechanisms Contributing to Enhanced NeuroHIV with Cocaine Use

Award Number: F31DA065449
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/19/2026
PERIOD OF PERFORMANCE END DATE: 02/18/2028

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Uncovering Mechanisms Contributing to Enhanced NeuroHIV with Cocaine Use - PROJECT SUMMARY Cocaine use disorder (CUD) is highly comorbid in people with HIV (PWH) and can accelerate infection, alter neuropathology, and exacerbate cognitive decline despite antiretroviral therapy (ART). Many of these effects are due to the infection and dysregulation of CNS-associated myeloid cells, especially microglia, which comprise a significant reservoir in this compartment. However, the precise mechanisms by which cocaine (Coc) dysregulates microglia to enhance HIV infection are unclear, partly due to the lack of translationally relevant human microglial models suitable for mechanistic evaluation of Coc-mediated changes in viral dynamics. Classically, Coc has been thought to act by blocking dopamine transporter (DAT) activity, exposing microglia to aberrantly high dopamine concentrations. Our data show that dopamine can increase HIV infection and inflammation in microglia and other myeloid cells. However, recent data show that Coc has other mechanisms of action beyond the modulation of dopaminergic tone, involving the ER protein sigma1 (σ1), which has diverse cellular functions including the modulation of cellular stress pathways such as the unfolded protein response (UPR). Viruses, including HIV, can exploit the UPR to amplify stress-induced protein production in the host cell, enhancing viral replication. Our preliminary studies indicate that Coc’s effects on σ1 may drive a Coc-mediated increase in HIV infection in microglia, potentially through increased stress response and independent of dopamine’s effects. My preliminary data show that both Coc and σ1 agonists increase HIV replication in human inducible pluripotent stem cell (iPSC)-derived microglia (iMg). These effects are blocked by σ1 antagonism but not by inhibition of DAT or dopamine receptors. We also show increased σ1 protein expression and recruitment to the ER/nuclear envelope space in HIV-infected iMg treated with Coc, and preliminary single-cell RNAseq data suggest changes in the UPR. Therefore, we hypothesize that Coc-mediated activation of σ1 increases HIV infection of microglia via activation of the UPR. In Aim 1, we will test the involvement of σ1 in driving Coc-mediated changes in HIV infection of iMg using pharmacological and genetic modulation, and we will also confirm the absence of dopaminergic involvement. We will assess changes in viral dynamics using AlphaLISA and immunofluorescence (IF) high-content imaging. In Aim 2, we will test the hypothesis that Coc induces greater σ1 activity in the presence of HIV infection utilizing confocal and high-content IF imaging of σ1 subcellular localization in cellular compartments like the nuclear envelope, ER, and mitochondria-associated ER membrane. Movement of σ1 to these compartments is a feature of σ1 activation. In Aim 3, we will use single-cell RNAseq to test the hypothesis that Coc-induced σ1 activity drives increased HIV infection in iMg via upregulation of UPR genes. The results from these experiments will not only define novel interactions between HIV and σ1 that could reveal new antiretroviral targets but will also broadly inform on the role of σ1 in microglia and potentially identify biomarkers for prevention strategies against CUD and its associated comorbid diseases.


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 = $48,996 )
2026	2026	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	001	1	3/25/2026	NEW	$576
2026	2026	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	1	2/19/2026	NEW	$48,420
2026	2026	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	002	1	3/25/2026	NEW	$0
														Subtotal = $48,996

Grand Total All Awards = $48,996

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Uncovering Mechanisms Contributing to Enhanced NeuroHIV with Cocaine Use

Award Number: F31DA065449

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/19/2026

PERIOD OF PERFORMANCE END DATE: 02/18/2028

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