The non-structural 5A protein of hepatitis C virus exhibits genotypic differences in interferon antagonism

Ya Hui Tsai; Wan Fen Kuang; Tsai Yi Lu; Jia Horng Kao; Ming Yang Lai; Chun Jen Liu; Pei Jer Chen; Lih Hwa Hwang

doi:10.1016/j.jhep.2008.06.030

The non-structural 5A protein of hepatitis C virus exhibits genotypic differences in interferon antagonism

Ya Hui Tsai, Wan Fen Kuang, Tsai Yi Lu, Jia Horng Kao, Ming Yang Lai, Chun Jen Liu, Pei Jer Chen, Lih Hwa Hwang^*

^*Corresponding author for this work

Institute of Microbiology and Immunology

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Background/Aims: 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.

Original language	English
Pages (from-to)	899-907
Number of pages	9
Journal	Journal of Hepatology
Volume	49
Issue number	6
DOIs	https://doi.org/10.1016/j.jhep.2008.06.030
State	Published - Dec 2008

Keywords

Genotype
Hepatitis C virus
IFN antagonism
NS5A

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jhep.2008.06.030

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@article{abf76d973cc64e9792241659d6dfe27d,

title = "The non-structural 5A protein of hepatitis C virus exhibits genotypic differences in interferon antagonism",

abstract = "Background/Aims: 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.",

keywords = "Genotype, Hepatitis C virus, IFN antagonism, NS5A",

author = "Tsai, {Ya Hui} and Kuang, {Wan Fen} and Lu, {Tsai Yi} and Kao, {Jia Horng} and Lai, {Ming Yang} and Liu, {Chun Jen} and Chen, {Pei Jer} and Hwang, {Lih Hwa}",

note = "Funding Information: We thank Dr. Takaji Wakita (Tokyo Metropolitan Institute for Neuroscience, Tokyo) for providing us with the pSGR-JFH1 and pSGR-JFH1/GND subgenomic replicons and Dr. Frank Chisari (Scripps Research Institute, La Jolla) for the Huh7.5.1 cell line. The work was supported by a grant from the National Science Council of the Republic of China (NSC 96-2752-B-002-004-PAE).",

year = "2008",

month = dec,

doi = "10.1016/j.jhep.2008.06.030",

language = "English",

volume = "49",

pages = "899--907",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier B.V.",

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TY - JOUR

T1 - The non-structural 5A protein of hepatitis C virus exhibits genotypic differences in interferon antagonism

AU - Tsai, Ya Hui

AU - Kuang, Wan Fen

AU - Lu, Tsai Yi

AU - Kao, Jia Horng

AU - Lai, Ming Yang

AU - Liu, Chun Jen

AU - Chen, Pei Jer

AU - Hwang, Lih Hwa

N1 - Funding Information: We thank Dr. Takaji Wakita (Tokyo Metropolitan Institute for Neuroscience, Tokyo) for providing us with the pSGR-JFH1 and pSGR-JFH1/GND subgenomic replicons and Dr. Frank Chisari (Scripps Research Institute, La Jolla) for the Huh7.5.1 cell line. The work was supported by a grant from the National Science Council of the Republic of China (NSC 96-2752-B-002-004-PAE).

PY - 2008/12

Y1 - 2008/12

N2 - Background/Aims: 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.

AB - Background/Aims: 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.

KW - Genotype

KW - Hepatitis C virus

KW - IFN antagonism

KW - NS5A

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DO - 10.1016/j.jhep.2008.06.030

M3 - Article

C2 - 18842320

AN - SCOPUS:84984559137

SN - 0168-8278

VL - 49

SP - 899

EP - 907

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 6

ER -

The non-structural 5A protein of hepatitis C virus exhibits genotypic differences in interferon antagonism

Abstract

Keywords

UN SDGs

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