Lenacapavir allosterically remodels the HIV-1 capsid.

Authors

Nayara F B Dos Santos, Jacob A Lewis, Mason Hansen, Miguel J B Pereira, Devin E Christensen, Wesley I Sundquist, Barbie K Ganser-Pornillos, Owen Pornillos

Published in

Science advances. Volume 12. Issue 36. Pages eaed8384. Sep 04, 2026. Epub Sep 02, 2026.

Abstract

Lenacapavir (LEN) is a highly potent, long-acting capsid inhibitor that holds exceptional promise for treatment and prevention of HIV-1 infection. LEN causes the mature viral capsid to rupture and lose integrity, but the underlying mechanism has been unclear. Here, we show that LEN is an allosteric modulator of HIV-1 capsid structure that fractures the capsid's fullerene cone architecture in two steps: initially by rupturing at high-curvature declinations, followed by fissuring of the capsid body. At the molecular level, LEN alters the noncovalent bonding interactions between capsid subunits and reduces local lattice curvature. We propose a stress-strain model to rationalize how LEN remodels HIV-1 capsid structure and thereby impairs the replication capacity of the virus.

PMID:
42685215
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.

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