Genetic and functional heterogeneity of the hepatitis C virus p7 ion channel during natural chronic infection

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.