title: The hepatitis C virus NS5A protein and response to interferon alpha: mutational analyses in patients with chronic HCV genotype 3a infection from India.
abstract: The hepatitis C virus (HCV) non-structural (NS)5A protein is linked to interferon alpha resistance in vitro and higher numbers of NS5A amino acid (aa) variations in HCV 1a/b isolates are associated with virologic response to interferon alpha-based therapy in vivo. Here, we aimed to study NS5A aa variations in Indian patients undergoing interferon alpha/ribavirin treatment infected with HCV 3a. The NS5A region [aa 2194-2401, comprising interferon sensitivity determining region, protein kinase resource (PKR) binding domain, V3 region] was sequenced from pre-treatment sera of 24 patients with HCV 3a infection. Mean number and physicochemical properties of aa variations (conserved vs. non-conserved) were assessed. Additionally, published NS5A sequences [NS5A region (n = 61), PKR binding domain (n = 111)] of characterized HCV 3a isolates were analyzed. The mean number of NS5A aa variations was not correlated with treatment response in our cohort. When all available NS5A sequences were included, a higher number of non-conserved aa variations within PKR binding domain and an extended V3 region of NS5A was associated with virologic response (P = 0.004 and 0.05, respectively). Mutational analyses of a large number of NS5A sequences suggest, that a higher number of non-conserved aa variations within the PKR binding domain and the extended V3 region is correlated with virologic response in HCV 3a infected patients.
authors.affiliation: Department of Gastroenterology, G.B. Pant Hospital, University of Delhi, New Delhi, India.
authors.forename: Ankur
authors.initials: A
authors.lastname: Goyal
authors.forename: Wolf P
authors.initials: WP
authors.lastname: Hofmann
authors.forename: Eva
authors.initials: E
authors.lastname: Hermann
authors.forename: Stella
authors.initials: S
authors.lastname: Traver
authors.forename: Syed S
authors.initials: SS
authors.lastname: Hissar
authors.forename: Naveen
authors.initials: N
authors.lastname: Arora
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
authors.forename: Shiv K
authors.initials: SK
authors.lastname: Sarin
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D015331:Cohort Studies; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D018936:Hepatitis C Antigens / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D007194:India; D016898:Interferon-alpha / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D017433:Protein Structure, Secondary; D012254:Ribavirin / Q000627:therapeutic use; D016415:Sequence Alignment; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D018936:Hepatitis C Antigens; D016898:Interferon-alpha; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase