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THE PRESENCE OF RESISTANCE MUTATIONS TO PROTEASE AND POLYMERASE INHIBITORS IN HEPATITIS C VIRUS SEQUENCES FROM THE LOS ALAMOS DATABANK
Hepatitis C virus
Polymerase
Protease
Resistance mutations
Hepacivirus/genética
Inibidores de Proteases/farmacologia
Proteínas não Estruturais Virais/genética
Substituição de Aminoácidos
Antivirais/farmacologia
Sequência de Bases
Domínio Catalítico
Bases de Dados Genéticas
Genótipo
Hepacivirus/efeitos de drogas
Hepacivirus/enzimologia
Hepatite C Crônica/quimioterapia
Humanos
Taxa de Mutação
Proteínas não Estruturais Virais/antagonistas & inibidores
Autor
Afiliación
Universidade Federal de São Paulo. Laboratório de Hepatologia Molecular Aplicada. Divisão de Gastroenterologia. Sao Paulo, SP, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Immunoparasitologia. Salvador, BA, Brasil
University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil
University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil
University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil
University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil
Universidade Federal de São Paulo. Laboratório de Hepatologia Molecular Aplicada. Divisão de Gastroenterologia. Sao Paulo, SP, Brasil
Universidade Federal de São Paulo. Laboratório de Hepatologia Molecular Aplicada. Divisão de Gastroenterologia. Sao Paulo, SP, Brasil / Instituto Butantan. Imunologia Viral. Sao Paulo, SP, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Immunoparasitologia. Salvador, BA, Brasil
University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil
University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil
University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil
University of Sao Paulo School of Medicine. Department of Gastroenterology. Sao Paulo, SP, Brasil
Universidade Federal de São Paulo. Laboratório de Hepatologia Molecular Aplicada. Divisão de Gastroenterologia. Sao Paulo, SP, Brasil
Universidade Federal de São Paulo. Laboratório de Hepatologia Molecular Aplicada. Divisão de Gastroenterologia. Sao Paulo, SP, Brasil / Instituto Butantan. Imunologia Viral. Sao Paulo, SP, Brasil
Resumen en ingles
Several new direct-acting antiviral (DAA) drugs are in development for chronic hepatitis C viral (HCV) infection, and NS3-NS4A serine protease and the NS5B RNA-dependent RNA polymerase have been the major targets. HCV variants displaying drug-resistant phenotypes have been observed both in vitro and during clinical trials. Our aim was to characterize amino acid changes at positions previously associated with resistance in protease (NS3) and polymerase (NS5B) regions from treatment-naïve HCV patients infected with genotypes 1a, 1b and 3a. All 1383 NS3 protease sequences (genotype 1a = 680, 1b = 498 and 3a = 205) and 806 NS5B polymerase sequences (genotypes 1a = 471, 1b = 329, 3a = 6) were collected from Los Alamos databank. Genotype 3a protease sequences showed the typical low-level resistance mutation V36L. NS3 sequences from other genotypes presented mutations on positions 36, 39, 41, 43, 54, 80, 109, 155 and 168 in a frequency lower than 2%, except for the mutation Q80R found in 35% of genotype 1a isolates. Polymerase sequences from genotype 3a patients showed five typical mutations: L419I, I424V, I482L, V499A and S556G. Two positions presented high polymorphism in the NS5B region from genotype 1a (V499A) and genotype 1b (C316N) subjects. Our results demonstrated a natural profile of genotype 3a that can be associated with the pre-existence of HCV variants resistant to first-generation protease inhibitors and to non-nucleoside polymerase inhibitors. Likewise, genotype 1b isolates and genotype 1a sequences exhibited pre-existing mutations associated with resistance to Palm II and Thumb I polymerase inhibitors, respectively.
Palabras clave en ingles
Direct-acting antiviral agentsHepatitis C virus
Polymerase
Protease
Resistance mutations
DeCS
Farmacorresistência ViralHepacivirus/genética
Inibidores de Proteases/farmacologia
Proteínas não Estruturais Virais/genética
Substituição de Aminoácidos
Antivirais/farmacologia
Sequência de Bases
Domínio Catalítico
Bases de Dados Genéticas
Genótipo
Hepacivirus/efeitos de drogas
Hepacivirus/enzimologia
Hepatite C Crônica/quimioterapia
Humanos
Taxa de Mutação
Proteínas não Estruturais Virais/antagonistas & inibidores
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