Autor segons l'article: Betancor G, Garriga C, Puertas MC, Nevot M, Anta L, Blanco JL, Pérez-Elías MJ, de Mendoza C, Martínez MA, Martinez-Picado J, Menéndez-Arias L,, Iribarren JA, Caballero E, Ribera E, Llibre JM, Clotet B, Jaén A, Dalmau D, Gatel JM, Peraire J, Vidal F, Vidal C, Riera M, Córdoba J, López Aldeguer J, Galindo MJ, Gutiérrez F, Álvarez M, García F, Pérez-Romero P, Viciana P, Leal M, Palomares JC, Pineda JA, Viciana I, Santos J, Rodríguez P, Gómez Sirvent JL, Gutiérrez C, Moreno S, Pérez-Olmeda M, Alcamí J, Rodríguez C, del Romero J, Cañizares A, Pedreira J, Miralles C, Ocampo A, Morano L, Aguilera A, Garrido C, Manuzza G, Poveda E, Soriano V Resistance Platform of the Spanish AIDS Research Network (ResRIS)
Departament: Medicina i Cirurgia
Autor/s de la URV: Peraire Forner, José Joaquin / SIRVENT CALVERA, JUAN JOSÉ / Vidal Marsal, Francisco
Paraules clau: Replication fitness Primer unblocking Nucleotide analogs Experienced patients Drug susceptibility Dna-synthesis Connection domain Confers zidovudine Combination antiretroviral therapy Amino-acid substitutions
Resum: 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. © 2012 Betancor et al.; licensee BioMed Central Ltd.
Àrees temàtiques: Virology Saúde coletiva Química Medicina veterinaria Medicina ii Medicina i Interdisciplinar Infectious diseases Farmacia Ciências biológicas iii Ciências biológicas i Biotecnología Biodiversidade
Accès a la llicència d'ús: https://creativecommons.org/licenses/by/3.0/es/
ISSN: 17424690
Adreça de correu electrònic de l'autor: joaquim.peraire@urv.cat francesc.vidal@urv.cat
Identificador de l'autor: 0000-0001-7808-5479 0000-0002-6692-6186
Data d'alta del registre: 2023-05-21
Versió de l'article dipositat: info:eu-repo/semantics/publishedVersion
Enllaç font original: https://retrovirology.biomedcentral.com/articles/10.1186/1742-4690-9-68
Referència a l'article segons font original: Retrovirology. 9 68-
Referència de l'ítem segons les normes APA: Betancor G, Garriga C, Puertas MC, Nevot M, Anta L, Blanco JL, Pérez-Elías MJ, de Mendoza C, Martínez MA, Martinez-Picado J, Menéndez-Arias L,, Iribar (2012). 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. Retrovirology, 9(), 68-. DOI: 10.1186/1742-4690-9-68
URL Document de llicència: https://repositori.urv.cat/ca/proteccio-de-dades/
DOI de l'article: 10.1186/1742-4690-9-68
Entitat: Universitat Rovira i Virgili
Any de publicació de la revista: 2012
Tipus de publicació: Journal Publications
Repositori URV