HIV-1 integrase interactions with viral RNA and capsid

The National Institute of Allergy and Infectious Diseases awarded The Francis Crick Institute Limited $150,000 on August 3, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855).

The award funds a two-year project investigating HIV-1 integrase interactions with viral RNA and capsid structures. The research focuses on defining the geometric and topological rules governing integrase filament positioning within the viral core lattice, refining the integrase-capsid interface to sufficient resolution to identify roles of individual amino acid residues, and mapping molecular interfaces mediating integrase-RNA interactions. These structural and mechanistic studies aim to inform development of next-generation allosteric integrase inhibitors and may reveal general principles of genome encapsidation applicable to other enveloped RNA viruses.

Performance occurs in Great Britain, United Kingdom. The period of performance runs through July 31, 2028.

Abstract

HIV-1 integrase promotes encapsidation of the viral genomic RNA within mature capsid cores, an essential, non- catalytic function that is a validated target for antiretroviral drug development. Allosteric integrase inhibitors disrupt this process, leading to mislocalization of viral RNA outside the core, causing catastrophic defects during reverse transcription after host cell entry. We recently discovered that integrase assembles into an RNA-binding filament that propagates along the inner wall of the viral core. This structure provides a conceptual basis for the non-catalytic functions of integrase and reveals previously unrecognized interactions between integrase and the HIV-1 capsid lattice. In this two-year project, we aim to define the geometric and topological rules that govern the positioning of in filaments within the conical fullerene CA lattice, refine the in-CA interface to a resolution sufficient to assign roles to individual amino acid side chains, and map the molecular interfaces that mediate the essential in-RNA interactions. These studies will provide a structural and mechanistic foundation for the second essential function of HIV-1 in. The results will inform the rational development of next-generation allosteric in inhibitors and may uncover general principles of genome encapsidation and maturation applicable to other enveloped RNA viruses.