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The presence of resistance mutations to protease and polymerase inhibitors in H epatitis C virus sequences from the L os A lamos databank
Author(s) -
Alves R.,
Queiroz A. T. L.,
Pessoa M. G.,
da Silva E. F.,
Mazo D. F. C.,
Carrilho F. J.,
CarvalhoFilho R. J.,
Carvalho I. M. V. G.
Publication year - 2013
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.12051
Subject(s) - genotype , polymerase , virology , biology , protease , hepatitis c virus , mutation , microbiology and biotechnology , rna polymerase , virus , genetics , gene , enzyme , rna , biochemistry
Summary Several new direct‐acting antiviral ( DAA ) drugs are in development for chronic hepatitis C viral ( HCV ) infection, and NS 3‐ NS 4A serine protease and the NS 5B 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 ( NS 3) and polymerase ( NS 5B) regions from treatment‐naïve HCV patients infected with genotypes 1a, 1b and 3a. All 1383 NS 3 protease sequences (genotype 1a = 680, 1b = 498 and 3a = 205) and 806 NS 5B 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. NS 3 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 NS 5B 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.