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The Role of Myeloid Cells in HIV Latency and Persistence in the Brain

Award Number: R01MH131441
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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The Role of Myeloid Cells in HIV Latency and Persistence in the Brain - Latently infected CD4+ T cells are considered to be the most important HIV reservoir preventing the implementation of an HIV cure. However, myeloid cells have been shown to be infected by HIV/SIV and to establish latency in animal models1-4. Therefore, elimination of the T cell reservoir alone is not likely to result in complete virus eradication. One of our long-term goals is to aid the development of effective HIV cure strategies by gaining a better understanding of the type and location of the cells that harbor replication competent HIV under ART suppression. HIV-associated neurological disorders or HAND affect up to 50% of people living with HIV (PLWH)5-7 suggesting that HIV-infected cells may persist in the brain of ART-suppressed individuals. HIV-DNA has been readily detected in the CSF of aviremic ART-suppressed PLWH and its presence is associated with poorer neurocognitive performance8. Analyses of brain tissue obtained postmortem from PLWH indicate that macrophages and microglia are major targets for HIV infection in the brain9-11 and demonstrate the presence of HIV-DNA+ cells in brain tissue from aviremic individuals10-12. Microglia are the predominant population of myeloid cells in the brain and in contrast to macrophages, are long lived and undergo cell division13,14. For these reasons, microglia are thought to represent a key cellular reservoir of HIV in the brain11. While there is a significant body of knowledge about the mechanisms of HIV latency and persistence in resting CD4+ T cells, there is significantly less known about HIV persistence in myeloid cells and therefore, a need to establish their possible role as a source of HIV reactivation after ART discontinuation. Specifically, in the brain the contribution of microglia is relatively unknown due in part to the difficulties in sampling cells in this compartment in PLWH. Our hypothesis is that HIV maintains a persistent reservoir in the brain under suppressive ART and our objective is to utilize an innovative humanized mouse model reconstituted with human brain microglia to increase the knowledge and understanding about how microglia contribute to HIV persistence and viral rebound by analyzing 1) HIV suppression by ART in human microglia in the brain, 2) the viral reservoir present in infected microglia, and 3) the development of HIV latency and rebound in human microglia in the brain after analytical therapy interruption. The new knowledge gained from the proposed experiments will contribute to a better understanding of HIV persistence in the brain, reactivation, and aid the development of novel HIV Cure approaches that target the CNS.


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 = $597,991 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	001	5	6/30/2025	NON-COMPETING CONTINUATION	$597,991
2025	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	2	2/13/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $597,991

Issue Date FY: 2024 ( Subtotal = $545,604 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	003	4	5/31/2024	NON-COMPETING CONTINUATION	$587,299
2024	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	001	3	1/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$450,339
2024	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Mental Health Research Grants	002	3	1/29/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	2	1/23/2024	NON-COMPETING CONTINUATION	-$492,034
														Subtotal = $545,604

Issue Date FY: 2023 ( Subtotal = $622,170 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	2	6/6/2023	NON-COMPETING CONTINUATION	$622,170
														Subtotal = $622,170

Issue Date FY: 2022 ( Subtotal = $705,172 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Mental Health Research Grants	000	1	8/31/2022	NEW	$705,172
														Subtotal = $705,172

Grand Total All Awards = $2,470,937

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The Role of Myeloid Cells in HIV Latency and Persistence in the Brain

Award Number: R01MH131441

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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