Two PKR inhibitor HCV proteins correlate with early but not sustained response to interferon.
OBJECTIVE
The NS5A and the E2 proteins of hepatitis C virus (HCV)-1b can bind and inhibit in vitro the interferon (IFN)-induced cellular kinase PKR. The role of such interaction in modulating the antiviral effect of IFN is still controversial. We have analyzed the E2 and the NS5A sequences in HCV-1b-infected patients treated with IFN to assess whether and how different combinations of wild-type and mutant proteins correlated with early and long-term virological response.


METHODS
In 30 patients, sequences of pretreatment and on-treatment E2-PePHD and NS5A-PKR binding domain (including the putative ISDR) were analyzed in parallel by sequencing cDNA-polymerase chain reaction products and up to 25 independent clones.


RESULTS
The E2-PePHD sequence was highly conserved with a homogeneous quasispecies and was identical in 29 of 30 cases with no association with the pattern of response and no evidence of evolution during therapy. Patients with a mutated NS5A-ISDR had a higher rate of early virological response (67%) than cases with wild-type ISDR (17%). This association was lost in long-term responders (33% vs. 17%).


CONCLUSIONS
Although the highly conserved E2-PePHD motif might contribute to reduce IFN responsiveness, variations within this region do not seem to play a role in modulating IFN sensitivity. The NS5A-ISDR sequence influenced the early, but not the sustained response, to IFN, suggesting that other factors may be more important for the long-term outcome of therapy.
Gerotto
M
M
Department of Clinical and Experimental Medicine, University of Padua, Padua, Italy.
Dal Pero
F
F
Pontisso
P
P
Noventa
F
F
Gatta
A
A
Alberti
A
A
D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D000998:Antiviral Agents / Q000627:therapeutic use*; D017124:Conserved Sequence / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006526:Hepatitis C / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D013997:Time Factors; D014759:Viral Envelope Proteins / Q000502:physiology*; D017361:Viral Nonstructural Proteins / Q000502:physiology*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D007372:Interferons; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; D019892:eIF-2 Kinase; C091015:glycoprotein E2, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase