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Role of capsid interactions with the viral RNA genome in assembly of HIV-1 cores

Award Number: R37AI203695
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: 08/18/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Role of capsid interactions with the viral RNA genome in assembly of HIV-1 cores - Project Summary During HIV-1 maturation, the Gag and Gag-Pol polyproteins undergo proteolytic processing to generate the structural and enzymatic components of the virion, including capsid (CA), nucleocapsid (NC), reverse transcriptase (RT), and integrase (IN). Individual CA molecules spontaneously assemble into the closed, fullerene cone-shaped structure termed capsid, which encapsulates the viral ribonucleoprotein complexes (vRNPs) composed of two copies of the viral RNA genome (vRNA), NC and viral replication enzymes RT and IN. HIV-1 CA performs multiple essential functions throughout the viral replication cycle, rendering it an attractive target for therapeutic intervention. This is exemplified by the recent clinical success of lenacapavir, a highly potent, long-acting capsid-targeting antiretroviral that was named Science’s Breakthrough of the Year in 2024. A comprehensive understanding of the diverse functions of CA is therefore critical not only for elucidating fundamental aspects of HIV-1 biology, but also for informing the rational development of next-generation capsid- targeting therapeutics. The fully mature fullerene capsid contains ~250 CA hexamers (CAHex) and 12 CA pentamers (CAPen). The capsid lattice is stabilized by a network of intra- and inter-hexameric CA-CA interactions as well as cellular cofactor inositol hexaphosphate (IP6) which binds to the central channels of CAHexs and CAPens. High resolution structures of the HIV-1 capsid shell have been elucidated. However, how vRNPs are encapsulated inside an HIV-1 core during maturation and the structural information for the luminal content of HIV-1 cores is lacking. We previously identified that HIV-1 IN binds the vRNA genome and demonstrated that IN-vRNA interactions are essential, but not sufficient, for virion morphogenesis. Here we provide preliminary structural biology, biochemistry and virology results which identify an unexpected, essential biological role of the luminal capsid surface to directly interact with vRNA during virion morphogenesis to enable encapsulation of vRNPs inside HIV-1 cores. The principal, outstanding questions to be addressed by our research are: what are structural and mechanistic bases for the encapsulation of vRNPs inside the protective, mature capsid? Which nucleoprotein interactions at the luminal side of the capsid are needed for virion morphogenesis? Accordingly, we propose to investigate the crucial nucleoprotein interactions between CA, vRNA and IN. Specifically, Aim 1 will elucidate the structural basis for interactions of CA hexamers with viral RNA and the biochemical mechanism of encapsulation of RNPs inside HIV-1 capsid. Aim 2 will dissect the molecular mechanism of CA-vRNA interactions in relevant physiological settings. Together, these studies will uncover new fundamental biology for how vRNPs are encapsulated by CA during HIV-1 maturation. Knowledge gained from these studies will aid the development of new CA-targeting therapeutics.


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 = $791,065 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	8/18/2026	NEW	$791,065
														Subtotal = $791,065

Grand Total All Awards = $791,065

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Role of capsid interactions with the viral RNA genome in assembly of HIV-1 cores

Award Number: R37AI203695

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: 08/18/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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