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Molecular investigations of HIV-1 maturation pathways and inhibitor actions in situ

Award Number: R01AI192025
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: 04/24/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Molecular investigations of HIV-1 maturation pathways and inhibitor actions in situ - PROJECT SUMMARY: The HIV-1 life cycle critically depends on a maturation process that transforms the viral core from a spherical to a conical shape, a crucial step for productive infection of host cells. This process is driven by the proteolytic cleavage of Gag and Gag-Pol polyproteins, resulting in the formation of the mature capsid. Although significant progress has been made in understanding Gag assembly and capsid structures, the dynamic transitions and molecular mechanisms underlying HIV-1 maturation remain inadequately understood, particularly within native cellular environments. To address these gaps, the Xiong laboratory has developed an advanced in situ cryo- electron microscopy (cryo-EM) approach, enabling high-resolution visualization of these processes in their native context. The research is structured around two specific aims: Aim 1 focuses on determining the high- resolution structural pathway of HIV-1 Gag assemblies and capsid during maturation within their native environment. This will involve using in situ cryo-EM and cryo-electron tomography (cryo-ET) to visualize the complex structural transitions of HIV-1 Gag and capsid during maturation. These studies will be conducted on both purified virus-like particles (VLPs) and budding viruses from infected cells, including clinically derived HIV- 1 isolates and primary CD4+ T cells. Preliminary data identify a novel hybrid capsid structure that may represent a transitional state in HIV-1 maturation, supporting the hypothesis of a replacive maturation pathway. This will be further tested through biochemical, structural, and functional experiments. Aim 2 will define the mechanisms by which HIV-1 capsid cofactors and maturation inhibitors influence virus maturation during budding. This will involve investigating how capsid inhibitors impact the maturation process using a comprehensive experimental system, including in vitro assembled Gag constructs, purified VLPs, and budding viruses on the cell surface. Preliminary findings have revealed new binding sites for Lenacapavir and a novel cellular cofactor within the immature Gag lattice. The cellular cofactor will be thoroughly investigated to determine its identity and function. The insights gained from this research will advance the understanding of HIV-1 maturation, guide the development of new therapeutic strategies targeting the immature Gag structures and the capsid, and provide valuable tools for studying host-virus interactions within their native cellular environments.


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 = $844,711 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	2	4/7/2026	NON-COMPETING CONTINUATION	$844,711
														Subtotal = $844,711

Issue Date FY: 2025 ( Subtotal = $859,992 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	1	4/24/2025	NEW	$859,992
														Subtotal = $859,992

Grand Total All Awards = $1,704,703

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Molecular investigations of HIV-1 maturation pathways and inhibitor actions in situ

Award Number: R01AI192025

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: 04/24/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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