Mechanistic basis for reduced viral and enzymatic fitness of HIV-1 reverse transcriptase containing both K65R and M184V mutations.
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.
Deval
Jérôme
J
Architecture et Fonction des Macromolécules Biologiques, UMR 6098 CNRS et Université Aix-Marseille I et II, ESIL, Campus de Luminy, 13288 Marseille cedex 09, France.
White
Kirsten L
KL
Miller
Michael D
MD
Parkin
Neil T
NT
Courcambeck
Jérôme
J
Halfon
Philippe
P
Selmi
Boulbaba
B
Boretto
Joëlle
J
Canard
Bruno
B
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000145:classification / Q000494:pharmacology*; D001665:Binding Sites; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010641:Phenotype; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D000068698:Tenofovir; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011994:Recombinant Proteins; D015215:Zidovudine; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000225:Adenine