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Productive and latent HIV infection of microglia: virus and host wrestle for SUMOylation system control

Award Number: R21MH134390
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Productive and latent HIV infection of microglia: virus and host wrestle for SUMOylation system control - Contact PD/PI: LANGFORD, T. DIANNE PROJECT SUMMARY This project will explore strategies to target epigenetic pathways for achieving sustained HIV remission and treatment of HIV associated-central nervous system (CNS) dysfunction. The conjugation of small ubiquitin- SUMO proteins to substrates is a well-described post-translational modification that regulates protein activity, subcellular localization, and protein-protein interactions for various downstream activities. SUMO proteins are also important in anti-viral immunity, opposing viral replication and mediating interferon-dependent anti-viral mechanisms. Thus, pathogens have evolved to exploit the host SUMOylation machinery to ensure viral persistence and pathogenesis. During infection, the human immunodeficiency virus type 1 (HIV-1) manipulates the host SUMOylation machinery to ensure its viral replication in CD4+ manipulates Microglia T cells, however, whether HIV-1 the SUMO paralogs to control its replication and/or atency in glial cells like microglia is unclear. are the main HIV-1 target cells in the CNS and constitute an important reservoir for viral pathogenesis. l In microglial cells, the co-repressor COUP-TF interacting protein 2 (CTIP2) recruits a multi-enzymatic chromatin- modifying complex and establishes a heterochromatic environment at the HIV-1 promoter, leading to HIV-1 silencing. Studies have shown that post-translational modifications (PTMs), including phosphorylation and SUMOylation, mediate CTIP2's interactions with other proteins and complexes. Similarly, tripartite motif- containing protein 28 (TRIM28), a known SUMO E3 ligase, associates with CTIP2 in the heterochromatin complex to inhibit HIV-1 viral replication. While regulating respectively, unknown. productive SUMOylation inducible SUMOylation and phosphorylation have been implicated in the activity of CTIP2 and TRIM28 in the context of T-cell signaling events and immune responses, the impact of PTMs in the initiation and establishment of HIV-1 latency in microglia remains To this end, this proposal's central hypothesis is that the host SUMOylation system is i mpaired during HIV-1 infection in microglia and that latency is established as a result of the estoration of of host proteins. To test this hypothesis , we will use immortalized human microglial cell lines and pluripotent stem cells (iPSCs), including a novel model of HIV-1 latency. r We will also identify the SUMO-modified proteome of human microglial cells during human HIV-1 infection. Project Summary/Abstract


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	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Mental Health Research Grants	000	2	1/28/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $163,625 )
2025	2025	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Mental Health Research Grants	001	2	3/5/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$163,625
2025	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Mental Health Research Grants	002	1	5/13/2025	NEW	$0
2025	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Mental Health Research Grants	000	1	3/5/2025	NEW	$0
														Subtotal = $163,625

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Mental Health Research Grants	000	1	8/7/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $237,750 )
2023	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Mental Health Research Grants	000	1	8/2/2023	NEW	$237,750
														Subtotal = $237,750

Grand Total All Awards = $401,375

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Productive and latent HIV infection of microglia: virus and host wrestle for SUMOylation system control

Award Number: R21MH134390

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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