Revolutionizing HIV treatment: unveiling the new frontiers of HIV capsid research

The HIV-1 capsid protein (CA) plays a crucial role in viral replication by orchestrating nuclear entry through interactions with host nuclear pore complexes (NPCs). Recent research has revealed that HIV-1 CA actively disrupts NPC architecture via phenylalanine-glycine (FG)-repeat nucleoporin interactions, thereby enabling nuclear translocation of viral components. This mechanistic insight has driven the development of lenacapavir, the first-in-class CA inhibitor approved for multidrug-resistant HIV-1. Lenacapavir competitively blocks CA-NPC binding, stabilizes cytoplasmic capsids, disrupts viral maturation, and demonstrates pan-stage antiviral efficacy and long-acting pharmacokinetics. Clinical trials have indicated its 100% prophylactic efficacy and potential to decrease global HIV incidence. Advances in structural biology, molecular dynamics simulations, and nanotechnology are expected to further inform next-generation therapeutic strategies targeting CA-host interactions. These findings not only redefine HIV-1 treatment paradigms but also have broader implications for combating CA-dependent viruses.