title: Involvement of novel human immunodeficiency virus type 1 reverse transcriptase mutations in the regulation of resistance to nucleoside inhibitors.
abstract: We characterized 16 additional mutations in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) whose role in drug resistance is still unknown by analyzing 1,906 plasma-derived HIV-1 subtype B pol sequences from 551 drug-naïve patients and 1,355 nucleoside RT inhibitor (NRTI)-treated patients. Twelve mutations positively associated with NRTI treatment strongly correlated both in pairs and in clusters with known NRTI resistance mutations on divergent evolutionary pathways. In particular, T39A, K43E/Q, K122E, E203K, and H208Y clustered with the nucleoside analogue mutation 1 cluster (NAM1; M41L+L210W+T215Y). Their copresence in this cluster was associated with an increase in thymidine analogue resistance. Moreover, treatment failure in the presence of K43E, K122E, or H208Y was significantly associated with higher viremia and lower CD4 cell count. Differently, D218E clustered with the NAM2 pathway (D67N+K70R+K219Q+T215F), and its presence in this cluster determined an increase in zidovudine resistance. In contrast, three mutations (V35I, I50V, and R83K) negatively associated with NRTI treatment showed negative correlations with NRTI resistance mutations and were associated with increased susceptibility to specific NRTIs. In particular, I50V negatively correlated with the lamivudine-selected mutation M184V and was associated with a decrease in M184V/lamivudine resistance, whereas R83K negatively correlated with both NAM1 and NAM2 clusters and was associated with a decrease in thymidine analogue resistance. Finally, the association pattern of the F214L polymorphism revealed its propensity for the NAM2 pathway and its strong negative association with the NAM1 pathway. Our study provides evidence of novel RT mutational patterns that regulate positively and/or negatively NRTI resistance and strongly suggests that other mutations beyond those currently known to confer resistance should be considered for improved prediction of clinical response to antiretroviral drugs.
authors.affiliation: Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Svicher
authors.forename: Tobias
authors.initials: T
authors.lastname: Sing
authors.forename: Maria Mercedes
authors.initials: MM
authors.lastname: Santoro
authors.forename: Federica
authors.initials: F
authors.lastname: Forbici
authors.forename: Fátima
authors.initials: F
authors.lastname: Rodríguez-Barrios
authors.forename: Ada
authors.initials: A
authors.lastname: Bertoli
authors.forename: Niko
authors.initials: N
authors.lastname: Beerenwinkel
authors.forename: Maria Concetta
authors.initials: MC
authors.lastname: Bellocchi
authors.forename: Federigo
authors.initials: F
authors.lastname: Gago
authors.forename: Antonella
authors.initials: A
authors.lastname: d'Arminio Monforte
authors.forename: Andrea
authors.initials: A
authors.lastname: Antinori
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.forename: Francesca
authors.initials: F
authors.lastname: Ceccherini-Silberstein
authors.forename: Carlo Federico
authors.initials: CF
authors.lastname: Perno
mesh_terms: D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008297:Male; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use
chemical_list: D018894:Reverse Transcriptase Inhibitors