The Effect of Mutations at Position E138 in HIV-1 Reverse Transcriptase and their Interactions with the M184I Mutation in Defining Patterns of Resistance to the Non-Nucleoside Reverse Transcriptase Inhibitors Rilpivirine and Etravirine.

Impacts of mutations at position E138(A/G/K/Q/R/V) alone or in combination with M184I in HIV-1 reverse transcriptase (RT) were investigated. We also determined why E138K is the most prevalent NNRTI mutation in patients failing RPV therapy. Recombinant RT enzymes and viruses containing each of the above-mentioned mutations were generated and drug susceptibility was assayed. Each of the E138 A/G/K/Q/R mutations, alone or in combination with M184I, resulted in decreased susceptibility to RPV and ETR. The maximum decrease in susceptibility to RPV was observed for E138/R/Q/G by both recombinant RT assay and cell-based assays. E138Q/R-containing enzymes and viruses also showed the most marked decrease in susceptibility to ETR by both assays. The addition of M184I to the E138 mutations did not significantly change levels of diminution in drug susceptibility. These findings indicate that E138R caused the highest level of loss of susceptibility to both RPV and ETR, and, accordingly, E138R should be recognized as an ETR resistance-associated mutation. The E138K/Q/R mutations can compensate M184I in regard to both enzymatic fitness and viral replication capacity. The favoured emergence of E138K over other mutations at position E138, together with M184I, is not due to an advantage in either level of drug resistance or viral replication capacity but may reflect the fact that E138R and E138Q require two distinct mutations to occur, one of which is a disfavorable G to C mutation, whereas E138K requires only a single favourable G to A hypermutation. Of course, other factors may also affect the concept of barrier to resistance.