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dc.contributor.authorSvicher, Valentina
dc.contributor.authorSing, Tobias
dc.contributor.authorSantoro, Maria Mercedes
dc.contributor.authorForbici, Federica
dc.contributor.authorRodríguez Barrios, Fátima 
dc.contributor.authorBertoli, Ada
dc.contributor.authorBeerenwinkel, Niko
dc.contributor.authorConcetta Bellocchi, Maria
dc.contributor.authorGago Badenas, Federico 
dc.contributor.authord'Arminio Monforte, Antonella
dc.contributor.authorAntinori, Andrea
dc.contributor.authorLengauer, Thomas
dc.contributor.authorCeccherini Silberstein, Francesca
dc.contributor.authorPerno, Carlo Federico
dc.date.accessioned2009-12-04T11:19:58Z
dc.date.available2009-12-04T11:19:58Z
dc.date.issued2006
dc.identifier.bibliographicCitationJOURNAL OF VIROLOGY, July 2006, p. 7186-7198en_US
dc.identifier.urihttp://hdl.handle.net/10017/5152
dc.description.abstractWe 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-naive 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, 150V, 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.en_US
dc.format.mimetypeapplication/pdfen
dc.language.isoengen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.titleInvolvement of novel human immunodeficiency virus type 1 reverse transcriptase mutations in the regulation of resistance to nucleoside inhibitorsen_US
dc.typeinfo:eu-repo/semantics/articleen
dc.subject.ecienciaCienciaes_ES
dc.subject.ecienciaFarmacologíaes_ES
dc.subject.ecienciaScienceen
dc.subject.ecienciaPharmacologyen
dc.contributor.affiliationUniversidad de Alcalá. Departamento de Farmacología
dc.relation.publisherversionhttp://dx.doi.org/10.1128/JVI.02084-05
dc.type.versioninfo:eu-repo/semantics/publishedVersionen_US
dc.identifier.doi10.1128/JVI.02084-05
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessen


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