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Opioid- and HIV-mediated effects on the integrity of the blood-brain barrier, on immune cell recruitment, and on antiretroviral penetration into thebrain

Award Number: R01DA053153
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Despite aggressive use of combination antiretroviral therapy, HIV infection is associated with cognitive and neurobehavioral impairment, collectively termed neuroHIV. HIV and opiates are independently associated with blood brain barrier (BBB) dysfunction, alterations in inflammatory signaling, and cognitive and motor deficits. The HIV viral protein Tat is thought to mediate much of the HIV-associated damage within the brain. This proposal will use both a Tat transgenic mouse model and a murine tropic HIV-infected mouse model. The Tat transgenic mouse model expresses HIV-1 Tat driven by a GFAP promotor, which limits expression to the CNS. The two models will be used to examine the effects of HIV and morphine in vivo. Our central hypothesis is that opiates compromise BBB function and contribute to neuropathology through complex mechanisms which include enhancing paracellular flux, while paradoxically decreasing net flux of antiretrovirals across the barrier, increasing infiltration of monocytes, and increasing inflammatory signals within the brain. We will address our hypotheses with the following specific aims. Aim 1. Define the effects of opiates ± HIV-1 Tat and HIV infection on BBB integrity and function and on region-specific impact on antiretrovirals and morphine concentrations within the brain. Aim 2. Characterize regional differences in the interplay between opiates ± HIV/HIV-1 Tat and ARVs on macrophage infiltration into the CNS and on proinflammatory cytokine production the CNS. These studies will define and relate the effects of opiates and/or HIV-1 on regional drug accumulation, BBB integrity, drug metabolism/efflux, and immune cell trafficking into and inflammatory signals within the brain. Better understanding of this dynamic interplay, with specific focus on antiretroviral brain concentrations, will improve the current therapeutic approaches for the HIV patients who use opioids (for licit or illicit use). The long-term goal is to understand how opiates limit ARV therapeutic efficacy within the brain in the setting of HIV and to identify targets for therapeutic development to eliminate the negative effects of opiates/HIV on neurocognitive outcomes.


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: 2024 ( Subtotal = $39,417 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Drug Abuse and Addiction Research Programs	002	4	2/8/2024	NON-COMPETING CONTINUATION	$354,764
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Drug Abuse and Addiction Research Programs	003	4	4/25/2024	NON-COMPETING CONTINUATION	$39,417
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Drug Abuse and Addiction Research Programs	004	4	7/23/2024	NON-COMPETING CONTINUATION	-$354,764
2024	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Drug Abuse and Addiction Research Programs	001	3	11/6/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$248,805
2024	2022	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Abuse and Addiction Research Programs	000	2	11/6/2023	NON-COMPETING CONTINUATION	-$248,805
														Subtotal = $39,417

Issue Date FY: 2023 ( Subtotal = $432,513 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Drug Abuse and Addiction Research Programs	001	3	5/12/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$432,513
2023	2022	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Abuse and Addiction Research Programs	000	2	5/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $432,513

Issue Date FY: 2022 ( Subtotal = $529,420 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Abuse and Addiction Research Programs	001	2	3/21/2022	NON-COMPETING CONTINUATION	$52,941
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Abuse and Addiction Research Programs	000	2	2/17/2022	NON-COMPETING CONTINUATION	$476,479
														Subtotal = $529,420

Issue Date FY: 2021 ( Subtotal = $533,985 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Drug Abuse and Addiction Research Programs	000	1	3/23/2021	NEW	$533,985
														Subtotal = $533,985

Grand Total All Awards = $1,535,335

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Opioid- and HIV-mediated effects on the integrity of the blood-brain barrier, on immune cell recruitment, and on antiretroviral penetration into thebrain

Award Number: R01DA053153

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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