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Clinical, virological and biochemical evidence supporting the association of HIV-1 reverse transcriptase polymorphism R284K and thymidine analogue resistance mutations M41L, L210W and T215Y in patients failing tenofovir/emtricitabine therapy. 2012
Gilberto Betancor, and
César Garriga, and
Maria C Puertas, and
María Nevot, and
Lourdes Anta, and
José L Blanco, and
M Jesús Pérez-Elías, and
Carmen de Mendoza, and
Miguel A Martínez, and
Javier Martinez-Picado, and
Luis Menéndez-Arias, and
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Estrella Caballero, and
Esteban Ribera, and
Josep Maria Llibre, and
Bonaventura Clotet, and
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David Dalmau, and
José María Gatel, and
Joaquín Peraire, and
Francesc Vidal, and
Carmen Vidal, and
Melchor Riera, and
Juan Córdoba, and
José López Aldeguer, and
María José Galindo, and
Félix Gutiérrez, and
Marta Álvarez, and
Federico García, and
Pilar Pérez-Romero, and
Pompeyo Viciana, and
Manuel Leal, and
José Carlos Palomares, and
Juan Antonio Pineda, and
Isabel Viciana, and
Jesús Santos, and
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Juan Luis Gómez Sirvent, and
Carolina Gutiérrez, and
Santiago Moreno, and
Mayte Pérez-Olmeda, and
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Carmen Rodríguez, and
Jorge del Romero, and
Angelina Cañizares, and
José Pedreira, and
Celia Miralles, and
Antonio Ocampo, and
Luis Morano, and
Antonio Aguilera, and
Carolina Garrido, and
Gustavo Manuzza, and
Eva Poveda, and
Vicente Soriano
Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid, Madrid, Spain.
BACKGROUND Thymidine analogue resistance mutations (TAMs) selected under treatment with nucleoside analogues generate two distinct genotypic profiles in the HIV-1 reverse transcriptase (RT): (i) TAM1: M41L, L210W and T215Y, and (ii) TAM2: D67N, K70R and K219E/Q, and sometimes T215F. Secondary mutations, including thumb subdomain polymorphisms (e.g. R284K) have been identified in association with TAMs. We have identified mutational clusters associated with virological failure during salvage therapy with tenofovir/emtricitabine-based regimens. In this context, we have studied the role of R284K as a secondary mutation associated with mutations of the TAM1 complex. RESULTS The cross-sectional study carried out with > 200 HIV-1 genotypes showed that virological failure to tenofovir/emtricitabine was strongly associated with the presence of M184V (P < 10-10) and TAMs (P < 10-3), while K65R was relatively uncommon in previously-treated patients failing antiretroviral therapy. Clusters of mutations were identified, and among them, the TAM1 complex showed the highest correlation coefficients. Covariation of TAM1 mutations and V118I, V179I, M184V and R284K was observed. Virological studies showed that the combination of R284K with TAM1 mutations confers a fitness advantage in the presence of zidovudine or tenofovir. Studies with recombinant HIV-1 RTs showed that when associated with TAM1 mutations, R284K had a minimal impact on zidovudine or tenofovir inhibition, and in their ability to excise the inhibitors from blocked DNA primers. However, the mutant RT M41L/L210W/T215Y/R284K showed an increased catalytic rate for nucleotide incorporation and a higher RNase H activity in comparison with WT and mutant M41L/L210W/T215Y RTs. These effects were consistent with its enhanced chain-terminated primer rescue on DNA/DNA template-primers, but not on RNA/DNA complexes, and can explain the higher fitness of HIV-1 having TAM1/R284K mutations. CONCLUSIONS Our study shows the association of R284K and TAM1 mutations in individuals failing therapy with tenofovir/emtricitabine, and unveils a novel mechanism by which secondary mutations are selected in the context of drug-resistance mutations.
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