title: Evidence for deleterious hepatitis C virus quasispecies mutation loads that differentiate the response patterns in IFN-based antiviral therapy.
abstract: Viral quasispecies (QS) have long been considered to affect the efficiency of hepatitis C virus (HCV) antiviral therapy, but a correlation between QS diversity and treatment outcomes has not been established conclusively. We previously measured HCV QS diversity by genome-wide quantification of high-resolution mutation load in HCV genotype 1a patients achieving a sustained virological response (1a/SVR) or a null response (1a/null). The current study extended this work into HCV 1a patients experiencing relapse (1a/relapse, n = 19) and genotype 2b patients with SVR (2b/SVR, n = 10). The mean mutation load per patient in 2b/SVR and 1a/relapse was similar, respectively, to 1a/SVR (517.6 ± 174.3 vs 524 ± 278.8 mutations, P = 0.95) and 1a/null (829.2 ± 282.8 vs 805.6 ± 270.7 mutations, P = 0.78). Notably, a deleterious mutation load, as indicated by the percentage of non-synonymous mutations, was highest in 2b/SVR (33.2 ± 8.5%) as compared with 1a/SVR (23.6 ± 7.8%, P = 0.002), 1a/null (18.2 ± 5.1%, P = 1.9 × 10(-7)) or 1a/relapse (17.8 ± 5.3%, P = 1.8) × 10(-6). In the 1a/relapse group, continuous virus evolution was observed with excessive accumulation of a deleterious load (17.8 ± 5.3% vs 35.4 ± 12.9%, P = 3.5 × 10(-6)), supporting the functionality of Muller's ratchet in a treatment-induced population bottleneck. Taken together, the magnitude of HCV mutation load, particularly the deleterious mutation load, provides an evolutionary explanation for the emergence of multiple response patterns as well as an overall high SVR rate in HCV genotype 2 patients. Augmentation of Muller's ratchet represents a potential strategy to reduce or even eliminate viral relapse in HCV antiviral therapy.
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA.|Wuhan Center for Tuberculosis Control, Wuhan 430030, Hubei, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA.
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA.
authors.forename: Yanjuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA.|Saint Louis University Liver Center, Saint Louis University School of Medicine, St Louis, MO 63104, USA.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Di Bisceglie
authors.affiliation: Division of Gastroenterology & Hepatology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63104, USA.|Saint Louis University Liver Center, Saint Louis University School of Medicine, St Louis, MO 63104, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Fan
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D007372:Interferons