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The Role of Endothelial Injury and Myeloid Cell Migration in the Activation of Inflammasomes in HIV infection and Cocaine Exposure

Award Number: R21DA059784
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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The Role of Endothelial Injury and Myeloid Cell Migration in the Activation of Inflammasomes in HIV infection and Cocaine Exposure - Combination anti-retroviral therapy (cART) reduces HIV-1 replication, viral load and increases survival of people living with HIV-1 (PLWH). PLWH who receive cART PLWH who receive cART are still under the risk of developing HIV-1-associated neurocognitive disorders (HAND). Chronic neuroinflammation is a critical factor for HAND pathogenesis. HIV-1 proteins (Tat, Vpr, Vpu and gp41) that expressed without HIV-1 replication induce inflammasome activation in chronic microglia and macrophages infection. Cocaine enhances HIV-1 replication in microglia in vitro. In HIV infected macrophages in the presence of cocaine, significant upregulation of NLRP3 gene and ROS production has been observed. Therefore, both cocaine and HIV-1 proteins may act synergistically to enhance inflammasome activation and neuroinflammation. We demonstrated that HIV-1 causes abnormal distribution of macrophages in the lungs of HIV-Tg mice after LPS administration, and inhibition of HIV-1 transcription restores normal macrophages distribution. Cocaine, which increases the permeability of the blood-brain barrier, may impact monocyte/macrophages migration. We hypothesize that cocaine exposure induces endothelial injury and increases accumulation of perivascular macrophages and microglia in HIV-Tg mice. We further hypothesize that HIV-1 proteins, cocaine, and DAMP signals from injured endothelial cells synergistically increase inflammasome activation. We propose that HIV-1 proteins will impair trans-endothelial migration of macrophages and reduce microglial migration towards the injured vessels, leading to prolonged inflammation. In Specific Aim 1, we will characterize myeloid cell populations in different brain locations in HIV- Tg mice under chronic cocaine treatment. We will evaluate a number, distribution and inflammasome activation in brain myeloid cells in HIV-Tg mice under cocaine exposure by immunostaining, RT-PCR and flow cytometry analysis of isolated myeloid cells. In Specific Aim 2, we will evaluate accumulation of perivascular macrophages and microglia around the vessels after cocaine exposure. We will test accumulation of macrophages and microglia around vessels after acute and chronic exposure of HIV-Tg mice to cocaine. Our hypothesis proposed in this application, if proven correct, would demonstrate that cocaine-induced endothelial damage enhances inflammasome activation and increases the accumulation of myeloid cells around vessels. The potential implications of this discovery could be used to develop novel therapeutic treatments that inhibit HIV-1 transcription or decrease brain endothelial injury.


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 = $0 )
2026	2025	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Drug Use and Addiction Research Programs	000	2	6/22/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $193,125 )
2025	2025	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Drug Use and Addiction Research Programs	002	2	8/1/2025	NON-COMPETING CONTINUATION	$193,125
2025	2024	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Drug Use and Addiction Research Programs	000	1	12/3/2024	NEW	$0
2025	2024	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Drug Use and Addiction Research Programs	001	1	12/13/2024	NEW	$0
														Subtotal = $193,125

Issue Date FY: 2024 ( Subtotal = $231,750 )
2024	2024	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Drug Use and Addiction Research Programs	000	1	9/19/2024	NEW	$231,750
														Subtotal = $231,750

Grand Total All Awards = $424,875

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The Role of Endothelial Injury and Myeloid Cell Migration in the Activation of Inflammasomes in HIV infection and Cocaine Exposure

Award Number: R21DA059784

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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