Journal Article

Strain and rupture of HIV-1 capsids during uncoating

Yu, Alvin, Voth, Gregory A., Pornillos, Owen, Lee, Elizabeth M. Y., Ganser-Pornillos, Barbie K., Briggs, John A. G.

2022

Overview

Viral replication in HIV-1 relies on a fullerene-shaped capsid to transport genetic material deep into the nucleus of an infected cell. Capsid stability is linked to the presence of cofactors, including inositol hexakisphosphates (IP₆) that bind to pores found in the capsid. Using extensive all-atom molecular dynamics simulations of HIV-1 cores imaged from cryo-electron tomography (cryo-ET) in intact virions, which contain IP₆ and a ribonucleoprotein complex, we find markedly striated patterns of strain on capsid lattices. The presence of these cofactors also increases rigidity of the capsid. Conformational analysis of capsid proteins (CA) show CA accommodates strain by locally flexing away from structures resolved using X-ray crystallography and cryo-ET. Then, cryo-ET of HIV-1 cores undergoing endogenous reverse transcription demonstrates that lattice strain increases in the capsid prior to mechanical failure and that the capsid ruptures by crack propagation along regions of high strain. These results uncover HIV-1 capsid properties involved in their critical disassembly process.

• Publisher: National Academy of Sciences
• Subject: Biological Sciences / Biophysics and Computational Biology / Capsid - chemistry / Capsid - physiology / Capsid Proteins - chemistry / Capsids / Cell Line / Chemistry / Cofactors / Conformational analysis / Cores / Crack propagation / Crystallography / Electron Microscope Tomography - methods / Flexing / Fullerenes / HIV / HIV-1 - physiology / Human immunodeficiency virus / Humans / Inositol / Inositols / Lattice strain / Lattices / Mechanical failure / Molecular dynamics / Molecular Dynamics Simulation / Physical Sciences / Protein Conformation / Reverse transcription / Rigidity / Uncoating / Virions / Virus Uncoating / X-ray crystallography