Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region.
We have previously demonstrated that sensitivity to interferon is different among hepatitis C virus (HCV) quasispecies simultaneously detected in same individuals and that interferon-resistant HCV quasispecies are selected during the treatment. To determine the genetic basis of their resistance to interferon, HCV genotype-1b was obtained from serum of three patients before and during interferon therapy, and their full-length nucleotide and deduced amino acid sequences were determined. Comparison of the pairs of interferon-resistant and interferon-sensitive HCV isolates in respective individuals demonstrated clusters of amino acid differences in the COOH-terminal half of the NS5A region (codon 2154-2383), which contained a common unique amino acid difference at codon 2218. Additional sequence data of the COOH-terminal half of the NS5A region obtained from six interferon-resistant and nine interferon-sensitive HCV confirmed the exclusive existence of missense mutations in a 40 amino acid stretch of the NS5A region around codon 2218 (from codon 2209 to 2248) in interferon-sensitive HCV. On the other hand, this region of interferon-resistant HCV was identical to that of prototype HCV genotype-1b (HCV-J, HCV-JTa, or HC-J4). We designated this region as the interferon sensitivity determining region. Thus, HCV genotype-1b with the prototype interferon sensitivity determining region appears to be interferon-resistant strains. The specific nature of these mutations might make it possible to predict prognostic effects of interferon treatment.
Enomoto
N
N
Second Department of Internal Medicine, Faculty of Medicine, Tokyo Medical and Dental University, Japan.
Sakuma
I
I
Asahina
Y
Y
Kurosaki
M
M
Murakami
T
T
Yamamoto
C
C
Izumi
N
N
Marumo
F
F
Sato
C
C
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D004351:Drug Resistance; D005260:Female; D016679:Genome, Viral; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000737:chemistry*; D012324:RNA-Dependent RNA Polymerase
D007372:Interferons; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase