Allosteric Crosstalk between Inhibitor Binding Sites Drives Enhanced Islatravir Susceptibility in F227C HIV-1 Reverse Transcriptase.

Doravirine (DOR) and islatravir (ISL) are inhibitors of human immunodeficiency virus type 1 (HIV-1) replication that block the viral reverse transcriptase (RT) by distinct mechanisms. The combination has demonstrated efficacy in Phase 3 clinical studies in both virologically suppressed and treatment-naïve people living with HIV-1 and has the potential to mitigate the emergence of resistance-associated mutations through complementary virological profiles. RT bearing a single point mutation, F227C, is associated with resistance to DOR, yet is hypersusceptible to ISL. Here, we report cryoEM structures of islatravir triphosphate (ISL-TP) bound to wild-type (WT) RT and F227C RT. Comparison with the corresponding ISL-TP and dATP-bound WT RT structures reveals that the F227C mutation induces an unexpected conformational change in a loop of the palm domain that is positioned to gate substrate access, providing a structural basis for ISL hypersusceptibility.