Dynamics of hepatitis C virus NS5A quasispecies during interferon and ribavirin therapy in responder and non-responder patients with genotype 1b chronic hepatitis C.
The quasispecies nature of hepatitis C virus (HCV) may have important implications concerning resistance to antiviral agents. To determine whether HCV NS5A quasispecies composition and dynamics are related to responsiveness to combined interferon (IFN) and ribavirin therapy, extensive sequence analyses of cloned RT-PCR amplification products of HCV-1b NS5A quasispecies of sequential isolates from 15 treated (nine sustained responders and six non-responders) and three untreated patients were performed. Accumulation of mutations in NS5A during therapy was relatively frequent in the V3 domain, but unusual elsewhere. Amino acid changes were the result of the imposition of minor variants that were already present before treatment and always occurred within the first week of therapy. Before treatment, the complexity and diversity of quasispecies were lower in isolates from responders than in those from non-responders, particularly in the V3 domain, where differences in nucleotide entropy (0.35 vs 0.64, P=0.003), genetic distance (0.0145 vs 0.0302, P=0.05) and non-synonymous substitutions (0.0102 vs 0.0203, P=0.036) were statistically significant. These differences became more apparent during treatment, because complexity and diversity remained stable or tended to increase in non-responders, whereas they tended to decrease in responders. These observations suggest that the composition and dynamics of HCV NS5A quasispecies, particularly in the V3 domain, may play a role in the response to combined IFN/ribavirin therapy.
Puig-Basagoiti
Francesc
F
Liver Unit, Institut de Malalties Digestives, Departament de Medicina (IMD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
Forns
Xavier
X
Liver Unit, Institut de Malalties Digestives, Departament de Medicina (IMD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
Furčić
Ivana
I
Liver Unit, Institut de Malalties Digestives, Departament de Medicina (IMD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
Ampurdanés
Sergi
S
Liver Unit, Institut de Malalties Digestives, Departament de Medicina (IMD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
Giménez-Barcons
Mireia
M
Liver Unit, Institut de Malalties Digestives, Departament de Medicina (IMD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
Franco
Sandra
S
Liver Unit, Institut de Malalties Digestives, Departament de Medicina (IMD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
Sánchez-Tapias
José M
JM
Liver Unit, Institut de Malalties Digestives, Departament de Medicina (IMD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
Saiz
Juan-Carlos
JC
Liver Unit, Institut de Malalties Digestives, Departament de Medicina (IMD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Spain.
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000145:classification / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D008969:Molecular Sequence Data; D009154:Mutation; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase