Lenacapavir allosterically remodels the HIV-1 capsid.

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.