title: Combined therapy of interferon plus ribavirin promotes multiple adaptive solutions in hepatitis C virus.
abstract: Hepatitis C virus (HCV) presents several regions involved potentially in evading antiviral treatment and host immune system. Two regions, known as PKR-BD and V3 domains, have been proposed to be involved in resistance to interferon. Additionally, hypervariable regions in the envelope E2 glycoprotein are also good candidates to participate in evasion from the immune system. In this study, we have used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples obtained just before initiation of therapy and after 6 or/and 12 months of treatment were available. A range of 25-100 clones per patient, genome region and time sample were obtained. The predominant amino acid sequences for each time sample and patient were determined. Next, the sequences of the PKR-BD and V3 domains and the hypervariable regions from different time samples were compared for each patient. The highest levels of variability were detected at the three hypervariable regions of the E2 protein and, to a lower extent, at the V3 domain of the NS5A protein. However, no clear patterns of adaptation to the host immune system or to antiviral treatment were detected. In summary, although high levels of variability are correlated to viral adaptive response, antiviral treatment does not seem to promote convergent adaptive changes. Consequently, other regions must be involved in evasion strategies likely based on a combination of multiple mechanisms, in which pools of changes along the HCV genome could confer viruses the ability to overcome strong selective pressures.
authors.affiliation: Departamento de Genética, Instituto Cavanilles de Biodiversidad y Biología Evolutiva, Universidad de Valencia, Valencia, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Cuevas
authors.forename: Manuela
authors.initials: M
authors.lastname: Torres-Puente
authors.forename: Nuria
authors.initials: N
authors.lastname: Jiménez-Hernández
authors.forename: María A
authors.initials: MA
authors.lastname: Bracho
authors.forename: Inmaculada
authors.initials: I
authors.lastname: García-Robles
authors.forename: Fernando
authors.initials: F
authors.lastname: Carnicer
authors.forename: Juan Del
authors.initials: JD
authors.lastname: Olmo
authors.forename: Enrique
authors.initials: E
authors.lastname: Ortega
authors.forename: Fernando
authors.initials: F
authors.lastname: González-Candelas
authors.forename: Andrés
authors.initials: A
authors.lastname: Moya
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use; D008969:Molecular Sequence Data; D009154:Mutation; D011994:Recombinant Proteins; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D017211:Treatment Failure; D014759:Viral Envelope Proteins / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012254:Ribavirin; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; C091015:glycoprotein E2, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase