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Molecular and cellular features governing antibody Fc-effector functions against HIV-1

Award Number: F31AI197926
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Molecular and cellular features governing antibody Fc-effector functions against HIV-1 - PROJECT SUMMARY HIV-1 remains a major global health challenge because current therapies cannot eliminate the persistent reservoir of infected cells. Overcoming this barrier requires broadly reactive strategies to eliminate infected cells. The HIV-1 envelope (Env) glycoprotein is difficult to target for broad neutralization. However, both broadly neutralizing and non-neutralizing antibodies can engage innate immune cells through their Fc domains. This activates Fc gamma receptor (FcγR) signaling, which drives antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). These immune functions can reduce viral reservoirs and have the potential to achieve long-term viral suppression without antiretrovirals. Fc-effector functions are therefore a promising HIV-1 cure strategy. However, the molecular and cellular features governing antibody Fc-effector functions against HIV-1 remain poorly understood. Addressing this gap in knowledge is essential for the development of more effective therapeutic and cure strategies for HIV-1. This proposal will test the hypothesis that specific molecular features of HIV-1 antibody interactions with Env determine FcγR signaling and Fc-effector function efficacy in ADCC and ADCP, using primary cells and transmitted/founder viral strains. Aim 1 tests whether Fc- effector function efficacy is determined by antibody capacity to crosslink HIV-1 Env and FcγRs at membrane- membrane interfaces. Flow virometry provides the unprecedented ability to directly monitor antibody aggregation of virions via Env crosslinking, supported by other biophysical assays. Preliminary virometry data shows that small molecule CD4 mimetic compounds (CD4mcs) enhance virion aggregation by non-neutralizing antibodies, consistent with Env crosslinking observed by cryoET and correlating with ADCC under these conditions. These assays, along with 4D live-cell microscopy, will be used to assess the role of Env and FcγR crosslinking in FcγR signaling and Fc-effector functions, using clinically relevant antibodies targeting different sites on HIV-1 Env with known levels of effector function, alongside crosslinking controls. Aim 2 investigates how differences in antibody crosslinking influence FcγR signaling efficiency and ADCC in NK cells versus ADCP in macrophages and neutrophils. 4D live-cell imaging will identify spatial and temporal features of these interactions, with preliminary imaging showing antibody clustering at the interface between cells expressing Env and NK cells under conditions known to mediate ADCC. Understanding how antibodies trigger immune clearance of HIV-infected cells will inform strategies for viral reservoir elimination and antibody-based HIV-1 therapies and cure approaches aligned with NIH priorities. The proposed training in the Department of Microbial Pathogenesis at Yale University will provide rigorous mentorship in structural virology, immunology, and advanced microscopy to support the applicant’s development toward a future career as an independent investigator at a research institution.


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 = $50,114 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	1	4/3/2026	NEW	$50,114
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	001	1	4/3/2026	NEW	$0
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Molecular and cellular features governing antibody Fc-effector functions against HIV-1

Award Number: F31AI197926

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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