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Benzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populations

Award Number: R01DA057337
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Benzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populations - One of the principal obstacles to curing HIV is the existence of viral reservoirs in distinct compartments and cell types that are unaffected by antiretroviral therapy (ART). In the central nervous system (CNS), these reservoirs are comprised of myeloid cells, such as perivascular macrophages and microglia. Critically, these reservoirs are generally established prior to the initiation of ART and the presence of ART in the CNS does not affect the established reservoir in long-lived myeloid populations. Thus, even in individuals on suppressive ART, persistently infected CNS macrophages and microglia can drive ongoing neuroinflammation and provide a source of HIV for viral recrudescence during medication hiatus or failure. Our ability to eliminate these reservoirs is severely limited by the lack of understanding of the transcriptional and epigenetic regulation of HIV in myeloid cells. To effectively target and eliminate CNS reservoirs in people living with HIV (PLWH), it is critical to define the transcriptional mechanisms mediating persistent infection in distinct CNS myeloid populations. The impact of HIV infection in the CNS is heightened in PLWH who have substance use disorders, including those who take and/or misuse therapeutic drugs such as benzodiazepines (BDZ). Benzodiazepines are used by more than 30 million Americans, have high abuse liability and misuse of these drugs accounts for 15 – 20% of their use. Benzodiazepines are prescribed to a growing number of PLWH and are associated with an increased risk of neurocognitive symptoms in this population. Little is known about the mechanisms by which BDZ impact HIV neuropathogenesis. Our published and preliminary data indicate that BDZ can alter the transcriptional regulation of HIV infection. To better understand and treat the development of neuroHIV in PLWH who use and/or misuse BDZ, it is vital to determine who benzodiazepines affect the transcriptional programs in myeloid cells. We hypothesize that both macrophages and microglia enter a semi-quiescent transcriptional state during ART exposure and that benzodiazepines disrupt this state and increase transcriptional activity and viral replication. Our data show that the BDZ Xanax, as well as some latency reactivation agents, mediate a dose-dependent increase in p24 production in infected, ART-treated cells. Our preliminary studies suggest these effects may result from BDZ interactions with the epigenetic regulator RUNX1. We posit that these changes in HIV replication in myeloid cells reflect the epigenetic state of the provirus. Thus, the growing population of PLWH who use BDZ is at greater risk of more severe neuropathogenesis. It also suggests that BDZ may provide the basis for novel therapeutics to manipulate HIV transcription in myeloid cells. Therefore, we will evaluate the transcriptional and epigenetic mechanisms sustaining the semi-quiescent state of HIV transcription in ART- treated human macrophages (Aim 1), define the differences in transcriptional and epigenetic processes in different types of myeloid cells using human syngeneic iPSC-derived macrophages and microglia (Aim 2), and examine the effect of benzodiazepines on transcription HIV-infected, ART-treated myeloid cells (Aim 3).


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 = $682,249 )
2025	2025	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	4	6/26/2025	NON-COMPETING CONTINUATION	$682,249
														Subtotal = $682,249

Issue Date FY: 2024 ( Subtotal = $682,249 )
2024	2024	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	3	5/24/2024	NON-COMPETING CONTINUATION	$682,249
														Subtotal = $682,249

Issue Date FY: 2023 ( Subtotal = $682,249 )
2023	2023	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	2	6/14/2023	NON-COMPETING CONTINUATION	$682,249
														Subtotal = $682,249

Issue Date FY: 2022 ( Subtotal = $695,124 )
2022	2022	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Drug Use and Addiction Research Programs	000	1	9/7/2022	NEW	$695,124
														Subtotal = $695,124

Grand Total All Awards = $2,741,871

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Benzodiazepine mediated mechanisms of transcriptional semi-quiescence in discrete myeloid populations

Award Number: R01DA057337

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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