A molecular switch modulates assembly and host factor binding of the HIV-1 capsid.

The HIV-1 capsid is a fullerene cone made of quasi-equivalent hexamers and pentamers of the viral CA protein. Typically, quasi-equivalent assembly of viral capsid subunits is controlled by a molecular switch. Here, we identify a Thr-Val-Gly-Gly motif that modulates CA hexamer/pentamer switching by folding into a 310 helix in the pentamer and random coil in the hexamer. Manipulating the coil/helix configuration of the motif allowed us to control pentamer and hexamer formation in a predictable manner, thus proving its function as a molecular switch. Importantly, the switch also remodels the common binding site for host factors that are critical for viral replication and the new ultra-potent HIV-1 inhibitor lenacapavir. This study reveals that a critical assembly element also modulates the post-assembly and viral replication functions of the HIV-1 capsid and provides new insights on capsid function and inhibition. © 2023. The Author(s).

Citation

Randall T Schirra, Nayara F B Dos Santos, Kaneil K Zadrozny, Iga Kucharska, Barbie K Ganser-Pornillos, Owen Pornillos. A molecular switch modulates assembly and host factor binding of the HIV-1 capsid. Nature structural & molecular biology. 2023 Mar;30(3):383-390

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PMID: 36759579

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