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Journal of Virology, October 2000, p. 9028-9038, Vol. 74, No. 19
Departments of Laboratory
Medicine1 and
Medicine,3 University of Washington,
Seattle, Washington, and Department of Medicine, Johns
Hopkins University School of Medicine, Baltimore,
Maryland2
Received 23 March 2000/Accepted 13 July 2000
The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein has
been controversially implicated in the inherent resistance of HCV to
interferon (IFN) antiviral therapy in clinical studies. In this study,
the relationship between NS5A mutations and selection pressures before
and during antiviral therapy and virologic response to therapy were
investigated. Full-length NS5A clones were sequenced from 20 HCV
genotype 1-infected patients in a prospective, randomized clinical
trial of IFN induction (daily) therapy and IFN plus ribavirin combination therapy. Pretreatment NS5A nucleotide and amino acid phylogenies did not correlate with clinical IFN responses and domains
involved in NS5A functions in vitro were all well conserved before and
during treatment. A consensus IFN sensitivity-determining region
(ISDR237-276) sequence associated with IFN resistance was
not found, although the presence of Ala245 within the ISDR was associated with nonresponse to treatment in genotype 1a-infected patients (P < 0.01). There were more mutations in the
26 amino acids downstream of the ISDR required for PKR binding in
pretreatment isolates from responders versus nonresponders in both
HCV-1a- and HCV-1b-infected patients (P < 0.05). In
HCV-1a patients, more amino acid changes were observed in isolates from
IFN-sensitive patients (P < 0.001), and the mutations
appeared to be concentrated in two variable regions in the C terminus
of NS5A, that corresponded to the previously described V3 region and a
new variable region, 310 to 330. Selection of pretreatment minor V3
quasispecies was observed within the first 2 to 6 weeks of therapy in
responders but not nonresponders, whereas the ISDR and PKR binding
domains did not change in either patient response group. These data
suggest that host-mediated selective pressures act primarily on the C terminus of NS5A and that NS5A can perturb or evade the IFN-induced antiviral response using sequences outside of the putative ISDR. Mechanistic studies are needed to address the role of the C terminus of
NS5A in HCV replication and antiviral resistance.
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Prospective Characterization of Full-Length Hepatitis C Virus
NS5A Quasispecies during Induction and Combination Antiviral
Therapy

*
Corresponding author. Mailing address: University of
Washington, Box 359690, 325 9th Ave., Seattle, WA 98104-2499. Phone: (206) 341-5224. Fax: (206) 341-5203. E-mail:
polyak{at}u.washington.edu.
Present address: Department of Hepato-Gastroenterology, University
of Brest, Brest, France.
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