The non-structural 5A protein of hepatitis C virus exhibits genotypic differences in interferon antagonism.
OBJECTIVE
Patients infected with hepatitis C virus (HCV) genotype 2 or 3 usually respond better to interferon (IFN) treatment than those infected with genotype 1. In this study, we investigated whether the non-structural 5A protein (NS5A) of HCV genotypes 1 and 2 (1b-NS5A and 2a-NS5A, respectively) exerted differential counteractivities against IFN treatment.


METHODS
We compared the inhibitory effects of 1b-NS5As and 2a-NS5As on IFN activity. We also investigated the replication inhibition of HCV subgenomic replicons containing 1b-NS5A or 2a-NS5A in response to IFN treatment.


RESULTS
1b-NS5As exerted more profound inhibitory effects on IFN activity than 2a-NS5As. The replication of the 2a-NS5A-containing replicons was more sensitive to IFN treatment than that of the 1b-NS5A-containing replicons. Deletion of the interferon sensitivity-determining region/protein kinase R-binding domain (PKR-BD), the V3 domain, or the C-terminus region of NS5A significantly abrogated its anti-IFN activity. Domain swapping between 1b-NS5A and 2a-NS5A in the V3 domain and/or the C-terminus region resulted in a transfer of their anti-IFN activity.


CONCLUSIONS
1b-NS5As exert higher magnitudes of IFN antagonism than do 2a-NS5As. The V3 and the C-terminus regions are responsible for the differential anti-IFN effects. This phenomenon may partly explain the genotype-linked differences in the response of HCV to IFN treatment.
Tsai
Ya-Hui
YH
Graduate Institute of Microbiology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
Kuang
Wan-Fen
WF
Lu
Tsai-Yi
TY
Kao
Jia-Horng
JH
Lai
Ming-Yang
MY
Liu
Chun-Jen
CJ
Chen
Pei-Jer
PJ
Hwang
Lih-Hwa
LH
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral / Q000235:genetics; D005838:Genotype; D006367:HeLa Cells; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D016898:Interferon-alpha; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase