Researchers published a Nature Communications study mapping recurrent and novel HIV-1 evolutionary pathways that confer resistance to lenacapavir, the long-acting capsid inhibitor. The team, led by Orris, Siddiqui, Tang and colleagues, identified multiple mutational trajectories the virus can adopt under drug pressure and characterized their effects on drug binding and viral fitness. The findings have immediate relevance for clinicians and drug developers deploying long-acting antiretrovirals: surveillance for emergent capsid mutations will be essential in populations receiving lenacapavir, and combination strategies or next-generation capsid-targeting chemotypes may be required to sustain durable suppression.