Evolution of hepatitis C virus quasispecies during ribavirin and interferon-alpha-2b combination therapy and interferon-alpha-2b monotherapy.
OBJECTIVE
Ribavirin and interferon combination therapy is more effective than interferon monotherapy in patients with chronic hepatitis C virus (HCV) infection. To test the hypothesis that ribavirin induces nucleotide substitutions in the viral genome and reduces viral load by forcing it into error catastrophe in the combination therapy, we investigated the molecular evolution of HCV quasispecies in 3 patients who received combination therapy and 2 patients who received interferon monotherapy.


METHODS
The quasispecies were analyzed before and after therapy by sequencing at least 8 clones in five regions of the HCV genome; 5' untranslated region, EI, E2, NS5A and NS5B.


RESULTS
Marked genetic drift was observed in the NS5A and NS5B regions in patients treated with combination therapy. However, genetic distances between clones obtained after therapy were closer than those obtained before therapy.


CONCLUSIONS
Our results suggest that the combination therapy modified HCV quasispecies, but that this did not reflect the induction of error catastrophe by ribavirin. Modification of quasispecies by this therapy requires further investigation in a larger number of patients to elucidate the possible mechanism of viral resistance against the combination therapy.
Arataki
Keiko
K
Department of Internal Medicine, Kure Medical Association Hospital, Kure-shi, and Department of Medicine and Molecular Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Japan.
Kumada
Hiromitsu
H
Toyota
Kiyomi
K
Ohishi
Waka
W
Takahashi
Shoichi
S
Tazuma
Susumu
S
Chayama
Kazuaki
K
D020121:5' Untranslated Regions / Q000235:genetics; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D019143:Evolution, Molecular; D040961:Genetic Drift; D016679:Genome, Viral; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009154:Mutation; D010802:Phylogeny; D011994:Recombinant Proteins; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D014759:Viral Envelope Proteins / Q000235:genetics; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
D020121:5' Untranslated Regions; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012254:Ribavirin; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; C087035:E1 protein, Hepatitis C virus; C091015:glycoprotein E2, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase