Lenacapavir treatment–emergent HIV-1 capsid resistance mutations are frequently associated with replication defects

Lenacapavir (LEN) is a long-acting HIV-1 capsid inhibitor that binds to the HIV-1 capsid protein with picomolar antiviral activity, disrupting its function and inhibiting viral replication. Here, we identified capsid mutations in samples from individuals treated with LEN across two clinical trials that were considered potential LEN resistance–associated mutations. The gag encoding regions of clinical isolates with capsid mutations, as well as associated site-directed mutants, were cloned into the infectious molecular clone pXXLAI and pNL4-3-JRFL-secNLuc, encoding replication-competent HIV-1. Their effects on LEN susceptibility, replication kinetics, and three-dimensional capsid structure were investigated.…

• GS
  Gilead Sciences