Suppression of La antigen exerts potential antiviral effects against hepatitis A virus

Xia Jiang; Tatsuo Kanda; Shuang Wu; Shingo Nakamoto; Kengo Saito; Hiroshi Shirasawa; Tomoko Kiyohara; Koji Ishii; Takaji Wakita; Hiroaki Okamoto; Osamu Yokosuka

doi:10.1371/journal.pone.0101993

Suppression of La antigen exerts potential antiviral effects against hepatitis A virus

PLoS One. 2014 Jul 7;9(7):e101993. doi: 10.1371/journal.pone.0101993. eCollection 2014.

Authors

Affiliations

¹ Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba, Japan.
² Department of Molecular Virology, Chiba University, Graduate School of Medicine, Chiba, Japan.
³ Department of Virology II, National Institute of Infectious Diseases, Musashimurayama, Japan.
⁴ Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Japan.

Abstract

Background: Despite the development and availability of hepatitis A virus (HAV) vaccine, HAV infection is still a major cause of acute hepatitis that occasionally leads to fatal liver disease. HAV internal ribosomal entry-site (IRES) is one of the attractive targets of antiviral agents against HAV. The aim of the present study is to evaluate the impact of La, one of the cellular proteins, on HAV IRES-mediated translation and HAV replication.

Methods and findings: We investigated the therapeutic feasibility of siRNAs specific for cellular cofactors for HAV IRES-mediated translation in cell culture. It was revealed that siRNA against La could inhibit HAV IRES activities as well as HAV subgenomic replication. We also found that the Janus kinase (JAK) inhibitors SD-1029 and AG490, which reduce La expression, could inhibit HAV IRES activities as well as HAV replication.

Conclusions: Inhibition of La by siRNAs and chemical agents could lead to the efficient inhibition of HAV IRES-mediated translation and HAV replication in cell culture models. La might play important roles in HAV replication and is being exploited as one of the therapeutic targets of host-targeting antivirals.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoantigens / genetics
Autoantigens / metabolism*
Cell Line, Tumor
Feasibility Studies
Gene Silencing
Genome, Viral / drug effects
Genome, Viral / genetics
Hepatitis A virus / genetics
Hepatitis A virus / physiology*
Humans
Janus Kinases / antagonists & inhibitors
Protein Biosynthesis / drug effects
Protein Biosynthesis / genetics
Protein Kinase Inhibitors / pharmacology
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Small Interfering / genetics
Ribonucleoproteins / deficiency
Ribonucleoproteins / genetics
Ribonucleoproteins / metabolism*
SS-B Antigen
Tyrphostins / pharmacology
Virus Replication / drug effects
Virus Replication / genetics
Xanthenes / pharmacology

Substances

Autoantigens
Protein Kinase Inhibitors
RNA, Messenger
RNA, Small Interfering
Ribonucleoproteins
SD 1029
Tyrphostins
Xanthenes
alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
Janus Kinases

Grants and funding

This work was supported by grants from the Ministry of Health, Labour and Welfare of Japan (H24-Hepatitis-General-002)(OY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.