title: Quasispecies of hepatitis C virus genotype 1 and treatment outcome with peginterferon and ribavirin.
abstract: The majority of patients with chronic hepatitis C fail to respond to antiviral therapy. The genetic basis of this resistance is unknown. The quasispecies nature of HCV may have an important implication concerning viral persistence and response to therapy. The HCV nonstructural 5A (NS5A) protein has been controversially implicated in the inherent resistance of HCV to interferon (IFN) antiviral therapy. To evaluate whether the NS5A quasispecies pre-treatment composition of HCV 1a/1b is related to responsiveness to combined pegylated interferon (PEG-IFN) and Ribavirin therapy, detailed analyses of the complete NS5A were performed. Fifteen full-length NS5A clones were sequenced from 11 pre-treatment samples of patients infected with genotype 1 HCV (3 virological sustained responders, 4 non-responders, and 4 end-of-treatment responders). Our study could not show a significant correlation between the mean number of mutations in HCV NS5A before treatment and treatment outcome, and the phylogenetic construction of complete NS5A sequences obtained from all patients failed to show any clustering associated with a specific response pattern. No single amino acid position was associated with different responses to therapy in any of the NS5A regions analyzed, and mutations were clustered downstream the ISDR, primarily in the V3 region. We observed that the CRS and NLS regions of the NS5A protein were conflicting for some variables analyzed, although no significant differences were found. If these two regions can have antagonistic functions, it seems viable that they present different mutation profiles when compared with treatment response. The patient sample that presented the lowest genetic distance values also presented the smallest number of variants, and the most heterogeneous pattern was seen in the end-of-treatment patients. These results suggest that a detailed molecular analysis of the NS5A region on a larger sample size may be necessary for understanding its role in the therapy outcome of HCV 1a/1b infection.
authors.affiliation: Department of Biology, Institute of Bioscience, Language & Literature and Exact Science, São Paulo State University, IBILCE - UNESP, São José do Rio Preto, SP, Brazil.
authors.forename: Ana Carolina Gomes
authors.initials: AC
authors.lastname: Jardim
authors.forename: Lílian Hiromi Tomonari
authors.initials: LH
authors.lastname: Yamasaki
authors.forename: Artur Trancoso Lopo
authors.initials: AT
authors.lastname: de Queiróz
authors.forename: Cíntia
authors.initials: C
authors.lastname: Bittar
authors.forename: João Renato Rebello
authors.initials: JR
authors.lastname: Pinho
authors.forename: Claudia Márcia Aparecida
authors.initials: CM
authors.lastname: Carareto
authors.forename: Paula
authors.initials: P
authors.lastname: Rahal
authors.forename: Isabel Maria Vicente Guedes de Carvalho
authors.initials: IM
authors.lastname: Mello
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000704:Analysis of Variance; D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010802:Phylogeny; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000627:therapeutic use*; D020539:Sequence Analysis, Protein; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C417083:peginterferon alfa-2b