Impact of HIV-1 capsid polymorphisms on viral infectivity and susceptibility to lenacapavir.

ABSTRACT: Lenacapavir (LEN) is a first-in-class capsid (CA) inhibitor for the treatment and prevention of HIV-1 infection. While LEN has shown potent antiviral activity across all major HIV-1 subtypes, the impact of existing HIV-1 CA sequence diversity on the activity of LEN remains to be determined. Here, we identified natural polymorphisms within the LEN-binding site and assessed each for their impact on viral infectivity and susceptibility to LEN. Using a co-crystal structure of LEN in complex with a CA hexamer, we identified 29 binding site residues within five angstroms of LEN and analyzed each for naturally occurring polymorphisms across a multiclade collection of >10,000 unique HIV-1 gag sequences. Eleven of these CA residues, including five (M66, Q67, K70, N74, and A105) previously as

SUBMITTER: Hansen D 

PROVIDER: S-EPMC12077089 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature