The presence of resistance mutations to protease and polymerase inhibitors in Hepatitis C virus sequences from the Los Alamos databank

Author(s)

Alves, R. ^[1] ; Queiroz, A. T. L. ^[2] ; Pessoa, M. G. ^[3] ; da Silva, E. F. ^[3] ; Mazo, D. F. C. ^[3] ; Carrilho, F. J. ^[3] ; Carvalho-Filho, R. J. ^[1] ; de Carvalho, I. M. V. G. ^{[4, 1]}

Affiliation

^[1] Univ Fed Sao Paulo, Div Gastroenterol, Setor Hepatites, Lab Hepatol Mol Aplicada, Sao Paulo - Brazil

^[2] CPqGM FIOCRUZ, Lab Imunoparasitol, Salvador, BA - Brazil

^[3] Univ Sao Paulo, Sch Med, Dept Gastroenterol, Sao Paulo - Brazil

^[4] Inst Butantan, Sao Paulo - Brazil

• Document type: Journal article
• Source: JOURNAL OF VIRAL HEPATITIS; v. 20, n. 6, p. 414-421, JUN 2013.
• Web of Science Citations: 36

Abstract

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-naive 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. (AU)

• FAPESP's process: 10/19054-5 - In silico analyses of primary mutations in sequences of cronical infected patients by HCV obtained from public databanks for resistance to the protease (NS3) and polymerase (NS5B) inhibitors.
• Grantee: Rafael Alves da Silva
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 09/14277-9 - HEPATITIS C VIRUS PRIMARY MUTATIONS RELATED TO RESISTANCE TO PROTEASE AND POLYMERASE INHIBITORS IN CHRONIC PATIENTS FROM SÃO PAULO CITY,BRAZIL
• Grantee: Isabel Maria Vicente Guedes de Carvalho Mello
• Support Opportunities: Regular Research Grants