Structural Basis for Dimeric Genome Selection by HIV-1
Year: 2026
Type: preprint
Abstract: ABSTRACT HIV-1 selects and packages a dimeric RNA genome into assembling virions, a requirement for strand transfer-mediated recombination during reverse transcription. Conserved RNA elements within the 5’-leader that promote dimerization and packaging have been identified (dimer initiation signal, DIS; core encapsidation signal, Ψ CES ; respectively), but the molecular mechanism that couples these processes remains unknown. Using an in vitro virus assembly assay, we show that dimeric HIV-1 5’-Leader RNAs promote assembly of viral Gag proteins into protein lattices resembling those of immature virions, whereas monomeric 5’-Leader constructs with similar affinities for Gag do not. Assembly requires the cellular factor, inositol hexakisphosphate, mimicking biology. Cryogenic electron microscopy (cryoEM) and tomography (cryoTM) studies of nascent assemblies are consistent with a structural model in which the dimeric DIS 2 helix bridges two elongated 6-helix bundles formed by the SP1 domains of adjacent Gag hexamers. The structure positions clusters of RNA-binding zinc knuckles from Gag’s nucleocapsid domain in close proximity to clusters of conserved guanosines shown here to be essential for genome packaging. Our findings suggest that DIS 2 functions as a molecular ruler, organizing Gag hexamers into structures optimized for Gag recruitment and Gag lattice expansion.
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7165195010