The M184I/V and K65R nucleoside resistance mutations in HIV-1 prevent the emergence of resistance mutations against dolutegravir.

Abstract

Recommended treatments for newly diagnosed HIV-positive individuals now focus on the integrase strand transfer inhibitors, raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG). In treatment-naive individuals, cases of RAL-based and EVG-based virological failure, although rare, are associated with the occurrence of resistance mutations in integrase and/or reverse transcriptase coding sequences. In such cases, common resistance substitutions in reverse transcriptase that were associated with nucleos(t)ide reverse transcriptase inhibitors included M184I/V and K65R and these occurred together with various mutations in integrase. In some instances, these mutations in reverse transcriptase preceded the emergence of mutations in integrase. In contrast, no resistance substitutions in either integrase or reverse transcriptase have been observed to date in viruses isolated from treatment-naive individuals who experienced treatment failure with DTG-based regimens. The objective of this study was to determine the effects of the M184I/V and K65R substitutions in reverse transcriptase on the ability of HIV-1 to become resistant against RAL, EVG or DTG. We performed tissue culture selection experiments using reverse transcriptase inhibitor-resistant viruses containing resistance substitutions at positions K65R, M184I or M184V in the presence of increasing concentrations of RAL, EVG or DTG and monitored changes in integrase sequences by genotyping. Selections using EVG and RAL led to the emergence of resistance mutations in integrase. In contrast, only the wild-type virus was able to acquire resistance mutations for DTG. Resistance mutations against nucleos(t)ide reverse transcriptase inhibitors antagonized the development of HIV-1 resistance against DTG but not RAL or EVG.