title: Genetic and functional heterogeneity of the hepatitis C virus p7 ion channel during natural chronic infection.
abstract: The present study describes natural genetic heterogeneity of hepatitis C virus (HCV) p7 protein, the ion channel that plays a critical role in assembly and release of HCV, within 299 variants isolated from serum specimens of 27 chronically infected patients, 12 of whom with human immunodeficiency virus (HIV) co-infection. Liver fibrosis stage was inversely correlated with p7 synonymous substitutions (dS) (p=0.033), and indices of p7 genetic diversity were significantly higher in HIV-negative subjects compared to HIV-positive subjects (dS, p=0.005; non-synonymous substitutions (dN), p=0.002; dN/dS ratio, p=0.024; amino acid distances, p=0.007). Six p7 genes with naturally occurring unique amino acid variations were selected for in vitro study. The variants demonstrated diversified functional heterogeneity in vitro, with one variant from a subject with severe liver disease displaying hyperactive ion channel function, as well as other variants presenting altered pH-activated channel gating activities.
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Atkins
authors.forename: Joseph
authors.initials: J
authors.lastname: Bruckner
authors.forename: Susan
authors.initials: S
authors.lastname: McArdle
authors.forename: Wan Chong
authors.initials: WC
authors.lastname: Qiu
authors.forename: Lisa V
authors.initials: LV
authors.lastname: Thomassen
authors.forename: John
authors.initials: J
authors.lastname: Scott
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Shuhart
authors.forename: Stephen
authors.initials: S
authors.lastname: Livingston
authors.forename: Lisa
authors.initials: L
authors.lastname: Townshend-Bulson
authors.forename: Brian J
authors.initials: BJ
authors.lastname: McMahon
authors.forename: Mark
authors.initials: M
authors.lastname: Harris
authors.forename: Stephen
authors.initials: S
authors.lastname: Griffin
authors.forename: David R
authors.initials: DR
authors.lastname: Gretch
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D005260:Female; D014644:Genetic Variation; D016174:Hepacivirus / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D019698:Hepatitis C, Chronic / Q000821:virology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D014764:Viral Proteins; C088369:p7 protein, Hepatitis C virus; D000086082:Viroporin Proteins