Title : Mechanistic Basis for Reduced Viral and Enzymatic Fitness of HIV-1 Reverse Transcriptase Containing Both K65R and M184V Mutations. Authors : Deval J, White KL, Miller MD, Parkin NT, Courcambeck J, Halfon P, Selmi B, Boretto J, Canard B. Abstract : Architecture et Fonction des Macromolecules Biologiques, UMR 6098 CNRS et Universite Aix-Marseille I et II, ESIL, Campus de Luminy, 13288 Marseille cedex 09, France, Gilead Sciences, Inc., Foster City, California, ViroLogic, Inc., S. San Francisco, California, and Genosciences, Marseille, France. HIV-1 drug resistance mutations are often inversely correlated with viral fitness, which remains poorly described at the molecular level. Some resistance mutations can also suppress resistance caused by other resistance mutations. We report the molecular mechanisms by which a virus resistant to lamivudine with the M184V reverse transcriptase mutation shows increased susceptibility to tenofovir and can suppress the effects of the tenofovir resistance mutation K65R. Additionally, we report how the decreased viral replication capacity of resistant viruses is directly linked to their decreased ability to use natural nucleotide substrates and that combination of the K65R and M184V resistance mutations leads to greater decreases in viral replication capacity. All together, these results define at the molecular level how nucleoside-resistant viruses can be driven to reduced viral fitness.