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Metabolic strategies to eliminate CNS Myeloid Viral Reservoirs

Award Number: R01MH128082
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Metabolic strategies to eliminate CNS Myeloid Viral Reservoirs - Abstract: HIV cure has not been achieved due to long-lasting latent HIV reservoirs that, upon ART interruption, reactivate the virus. The best characterized viral reservoirs are different circulating subpopulations of T lymphocytes, but it has become evident that most viral reservoirs are localized in several tissues, including the brain. However, little is known about HIV persistence in myeloid cells, becoming a controversial issue. Only recently, genetic phylogenetic analysis indicates that viral reactivation cannot be explained by CD4 T containing the virus. Thus, alternative reservoirs need to be considered, such as a myeloid cell. Myeloid tissue-associated cells have multiple advantages over T cells to consider long-lasting viral reservoirs including tissue location, long-life, slow turn around, and higher resistance to apoptosis compared to T cells. In the brain, microglia and macrophages are the main cell type with HIV-integrated. Our data identify macrophage/microglia as a key viral reservoir within the brain, even in long-term ART. We developed an in vitro system to generate latent infected microglia or macrophages that can be reactivated by multiple treatments, including Meth, LPS, and LRA. The latently HIV-infected macrophages/microglia cells survive infection by blocking the apoptosome's formation by increasing bim protein expression, preventing further apoptosis. Further, we identified that latently HIV-infected cells (microglia/macrophages) had a unique metabolic signature that relies on glutamate/glutamine for ATP production and survival. More surprising is that HIV reservoirs cannot switch between different carbon sources such as lipids, glucose, or unusual sources of carbon like amino acids like uninfected cells. Blocking these metabolic pathways results in significant apoptosis of HIV reservoirs even in the absence of reactivation. Our results will provide a better understanding of the mechanisms that regulate the generation and survival of HIV myeloid reservoirs within the CNS and provide essential information for eradicating these viral reservoirs from 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 = $425,936 )
2025	2025	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Mental Health Research Grants	000	5	4/30/2025	NON-COMPETING CONTINUATION	$425,936
														Subtotal = $425,936

Issue Date FY: 2024 ( Subtotal = $687,604 )
2024	2024	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Mental Health Research Grants	000	4	5/2/2024	NON-COMPETING CONTINUATION	$687,604
														Subtotal = $687,604

Issue Date FY: 2023 ( Subtotal = $690,484 )
2023	2023	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Mental Health Research Grants	000	3	5/9/2023	NON-COMPETING CONTINUATION	$690,484
														Subtotal = $690,484

Issue Date FY: 2022 ( Subtotal = $705,484 )
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Mental Health Research Grants	000	2	5/27/2022	NON-COMPETING CONTINUATION	$705,484
														Subtotal = $705,484

Issue Date FY: 2021 ( Subtotal = $559,396 )
2021	2021	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Mental Health Research Grants	000	1	7/29/2021	NEW	$559,396
														Subtotal = $559,396

Grand Total All Awards = $3,068,904

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Metabolic strategies to eliminate CNS Myeloid Viral Reservoirs

Award Number: R01MH128082

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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