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Characterization of HIV persistence and neuroinflammation in the CNS reservoir in vivo

Award Number: R01MH143145
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Characterization of HIV persistence and neuroinflammation in the CNS reservoir in vivo - HIV persists in central nervous system (CNS) reservoirs despite effective combination antiretroviral therapy (ART), contributing to chronic neuroinflammation and neuropathogenesis. While macrophages and microglia are known cellular reservoirs in the CNS, recent evidence suggests that infiltrating T cells also play a critical role in sustaining viral persistence. Limited access to human CNS tissues hampers our understanding of contributions of the CNS T cell reservoir in HIV neuropathogenesis. To closely examine the effects of HIV infection in the CNS, we will leverage a unique barcoded HIV system in a novel humanized mouse model to study CNS-resident viral reservoirs. Our preliminary data demonstrate that this barcoded HIV, which allows us to track and characterize virus that is being produced from different anatomic reservoirs, establishes a robust infection in both peripheral and CNS tissues, with RNA sequencing revealing upregulated type I interferon signaling and microglial activation, indicating HIV driven chronic neuroinflammation in vivo. Additionally, we have previously demonstrated in non-human primate (NHP) studies that HIV-specific chimeric antigen receptor (CAR) T cells that developed from gene modified hematopoietic stem/progenitor cells (HSPCs) can traffic to the CNS and reduce viral burden, indicating that there are ways to specifically deliver therapeutic antiviral T cells to the CNS. These findings highlight a need to define the mechanisms underlying T cell-mediated viral persistence in the CNS and to optimize CNS reservoir-targeted therapies. In these studies, we propose an integrated approach using barcoded HIV tracking, spatial transcriptomics, single-cell RNA sequencing, and integration site analysis to investigate the contributions of T cell populations in HIV persistence and inflammation in the CNS. Our central hypothesis is that T cells serve as key latent reservoirs in the CNS, promoting chronic immune activation, and that HSPC-derived CAR T cell therapy can effectively target and reduce these reservoirs. To test this hypothesis, we will: 1) Assess T cell reservoirs in the CNS during acute and chronic phase of HIV infection in humanized mice infected with barcoded HIV. 2) Investigate the contributions of T cell populations on CNS inflammation and neuropathogenesis during HIV infection. 3) Evaluate the antigen-specific T cell responses and therapeutic effects of CAR T cells on viral reservoir clearance and neuropathogenesis in the CNS. This study will provide critical insights into the role and consequences of T cell-mediated HIV persistence in the CNS and assess CAR T cells as a novel strategy for reservoir clearance and neuroinflammation reduction, advancing HIV cure strategies.


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 = $787,498 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Mental Health Research Grants	000	1	6/25/2026	NEW	$787,498
														Subtotal = $787,498

Grand Total All Awards = $787,498

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Characterization of HIV persistence and neuroinflammation in the CNS reservoir in vivo

Award Number: R01MH143145

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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