A Nature Communications study traced recurrent and unique evolutionary routes by which HIV‑1 develops resistance to lenacapavir, a long‑acting capsid inhibitor. The research identified specific capsid mutations and adaptive pathways that reduce drug susceptibility and may compromise clinical durability of lenacapavir‑based regimens. Authors Orris, Siddiqui, Tang and colleagues used longitudinal sequencing and in‑vitro selection to reveal both common escape mutations and novel compensatory changes. The findings underscore the need for molecular surveillance, combination strategies to suppress resistance, and next‑generation capsid inhibitor design.