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Adv."],"published-print":{"date-parts":[[2026,9,4]]},"abstract":"<jats:p>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\u2019s 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. 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