Genetic variability of hepatitis C virus before and after combined therapy of interferon plus ribavirin.
We present an analysis of the selective forces acting on two hepatitis C virus genome regions previously postulated to be involved in the viral response to combined antiviral therapy. One includes the three hypervariable regions in the envelope E2 glycoprotein, and the other encompasses the PKR binding domain and the V3 domain in the NS5A region. We used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples were obtained before initiation of therapy and after 6 or/and 12 months of treatment. A range of 25-100 clones per patient, genome region and time sample were sequenced. These were used to detect general patterns of adaptation, to identify particular adaptation mechanisms and to analyze the patterns of evolutionary change in both genome regions. These analyses failed to detect a common adaptive mechanism for the lack of response to antiviral treatment in these patients. On the contrary, a wide range of situations were observed, from patients showing no positively selected sites to others with many, and with completely different topologies in the reconstructed phylogenetic trees. Altogether, these results suggest that viral strategies to evade selection pressure from the immune system and antiviral therapies do not result from a single mechanism and they are likely based on a range of different alternatives, in which several different changes, or their combination, along the HCV genome confer viruses the ability to overcome strong selective pressures.
Cuevas
José Manuel
JM
Instituto Cavanilles de Biodiversidad y Biología Evolutiva and Departamento de Genética, Universidad de Valencia, Valencia, Spain.
Torres-Puente
Manuela
M
Jiménez-Hernández
Nuria
N
Bracho
María Alma
MA
García-Robles
Inmaculada
I
Wrobel
Boris
B
Carnicer
Fernando
F
del Olmo
Juan
J
Ortega
Enrique
E
Moya
Andrés
A
González-Candelas
Fernando
F
D000998:Antiviral Agents / Q000627:therapeutic use*; D022801:Complementarity Determining Regions / Q000187:drug effects; D019143:Evolution, Molecular; D014644:Genetic Variation / Q000187:drug effects; D016679:Genome, Viral / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D010802:Phylogeny; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000187:drug effects / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D022801:Complementarity Determining Regions; 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