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Host Restriction of Immune Escape HIV-1 Mutants

Award Number: R56AI200599
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/07/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Host Restriction of Immune Escape HIV-1 Mutants - Project Summary Neither a vaccine nor a scalable cure is available to end the HIV/AIDS pandemic. A feasible “functional cure” approach entails durable antiretroviral therapy-free control of HIV, a characteristic exhibited by HIV elite controllers (ECs). In certain ECs carrying human leukocyte antigen B27, potent CD8+ cytotoxic T-lymphocyte (CTL) response targeting the HIV-1 capsid protein (CA) epitope KK-10 establishes a functional cure-like status. The selection of CTL escape CA mutation R264K significantly diminishes virus replication, which intriguingly is contingent on two critical CA-binding host dependency factors—cyclophilin A (CypA) and cleavage and polyadenylation specificity factor subunit 6 (CPSF6). Eventually, selection of compensatory CA mutation S173A restores R264K-harboring virus replication to WT levels in these ECs. The underlying virus- host cell dynamics remains largely undetermined. Our long-term goal is to understand the molecular mechanisms that impose immune control of HIV-1 and that enable HIV-1’s counter response and immune escape. Our previous work demonstrated that R264K-linked infectivity defect results from CypA-dependent impairment of viral DNA integration but is restored by the presence of CA mutation S173A or the absence of CypA. The objective of this proposal is to determine the mechanistic basis of the novel host dependency factor-dictated R264K-imposed virus integration block and the S173A-associated restoration of viral integration. Our central hypothesis is that the R264K-harboring virus integration impairment is imposed by the human anti-HIV restriction protein TRIM5αhu in a CypA- or CPSF6-dependent manner and that the compensatory CA mutation S173A restores viral integration by altering R264K capsid conformation that renders it inaccessible to TRIM5αhu restriction. The rationale is based on our published data demonstrating direct functional role for CA, CypA, and CPSF6 in HIV-1 integration as well as published findings by other research groups. Our work is innovative as it probes a host dependency factor-guided HIV restriction by nuclear-localized TRIM5αhu. In the proposed project, we will study the effect of HIV-1 nuclear PIC-associated CypA or CPSF6 on R264K-imposed impairment of viral integration (Aim 1), the proposed role of nuclear TRIM5αhu in R264K- imposed virus integration block (Aim 2), and the predicted consequence of S173A-associated capsid core conformational changes on TRIM5αhu restriction and the restoration of R264K-harboring virus integration (Aim 3). The proposed research is significant because of its potential to yield fundamental insights into novel mechanisms of virus/host cell dynamics governing the replication outcomes of clinically significant immune escape HIV-1 mutants and will broadly impact the field by supporting the development of innovative cure and treatment strategies for controlling the HIV/AIDS pandemic. 1


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 = $613,261 )
2026	2026	MEHARRY MEDICAL COLLEGE	1005 DR DB TODD JR BLVD	NASHVILLE	TN	37208	DAVIDSON	USA	Allergy and Infectious Diseases Research	000	1	5/11/2026	NEW	$613,261
														Subtotal = $613,261

Grand Total All Awards = $613,261

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Host Restriction of Immune Escape HIV-1 Mutants

Award Number: R56AI200599

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/07/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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