TREATING HIV INFECTION, WHEREIN HIV HAS A K65R MUTATION

摘要

Nucleotide-competing reverse transcriptase inhibitors (NcRTI) bind to the active site of HIV reverse transcriptase (RT) in competition with the next incoming nucleotide. To further investigate the impact of RT inhibitor resistance mutations on the activity of NcRTIs, the susceptibility of > 6000 recent clinical isolates for a prototype compound, NcRTI-1, was determined. Over 80% of the profiled clinical isolates remained susceptible for NcRTI-1 (FC < 4). No cross-resistance was observed between NcRTI-1 and currently used RT inhibitors, apart from limited cross-resistance with 3TC/FTC. Analysis of the genotype of > 1700 of these viruses showed that the combination of active site mutations M184V + Y115F correlated most with resistance to NcRTI-1 (FC = 75). Analysis also indicated that the K65R mutation is associated with hypersusceptibility to NcRTI-1 and that it reverses the reduced susceptibility caused by 20 M184V. These findings were confirmed in SDM strains. This reciprocity between the K65R and M184V mutation is unparalleled among RT inhibitors. When replicating wild-type HIV-1 in the presence of NcRTI-1, M184V + Y115F were selected. In the presence of both NcRTI-1 and tenofovir, NcRTI-1 prevents the selection of K65R.