Sequence analysis of PePHD within HCV E2 region and correlation with resistance of interferon therapy in Japanese patients infected with HCV genotypes 2a and 2b.
OBJECTIVE
Hepatitis C virus (HCV) E2 protein was recently reported to have a double-stranded RNA-activated protein kinase-eukaryotic initiation factor 2alpha (PKR-eIF2alpha) phosphorylation homology domain (PePHD); PKR is induced by interferon (IFN). PePHD interacts with PKR and inactivates it. PePHD could be a predictor for IFN response, like the interferon sensitivity determination region (ISDR) of HCV NS5A. Several groups reported that PePHD is conserved, and mutations in this region do not correlate with IFN response. In this study, we further investigated the amino acid variation of PePHD among four major genotypes and its correlation with IFN response.


METHODS
We enrolled 74 patients for this study and determined PePHD sequence of HCV derived from sera of patients infected with HCV genotype 1a (1 patient; nonresponder [NR]), 1b (36 patients; 4 complete responders [CR], 32 NR), 2a (29 patients; 17 CR, 12 NR), and 2b (8 patients; 3 CR, 5 NR). We also analyzed mutations in ISDR of HCV genotype 1b in 31 patients.


RESULTS
PePHD had several variations among four genotypes investigated. In patients infected with HCV genotype 1b, PePHD sequence was well conserved and seemed to have no correlation with IFN response. Mutations in ISDR were correlated with IFN response. In patients with HCV genotypes 2a and 2b, PePHD had multiple variations, and one particular motif, "RGQQ-" at the N-terminus, showed a close correlation with IFN resistance. All eight patients with HCV containing this motif were IFN nonresponders.


CONCLUSIONS
IFN resistance of HCV correlates with its "RGQQ-" motif at the N-terminus of PePHD in HCV genotype 2a and 2b. PePHD of HCV could be a predictor of IFN resistance in patients infected with HCV genotype 2a and 2b.
Saito
Takeshi
T
Second Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan.
Ito
Takayoshi
T
Ishiko
Hiroaki
H
Yonaha
Mari
M
Morikawa
Kenichi
K
Miyokawa
Akio
A
Mitamura
Keiji
K
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D017124:Conserved Sequence; D024882:Drug Resistance, Viral / Q000235:genetics*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy; D018936:Hepatitis C Antigens / Q000235:genetics*; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid; D014759:Viral Envelope Proteins / Q000235:genetics*; D019892:eIF-2 Kinase / Q000235:genetics*
D000998:Antiviral Agents; D015852:Eukaryotic Initiation Factor-2; D018936:Hepatitis C Antigens; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus; D007372:Interferons; D019892:eIF-2 Kinase