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Immunity. 2015 Jan 20;42(1):123-32. doi: 10.1016/j.immuni.2014.12.016. Epub 2014 Dec 18.

The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus.

Author information

1
Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan; Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan.
2
Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan.
3
PhoenixBio Co., Ltd., Higashihiroshima, Hiroshima 739-0046, Japan.
4
Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan.
5
Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
6
Department of Virology II, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
7
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA.
8
Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
9
Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan; Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan. Electronic address: takaoka@igm.hokudai.ac.jp.

Abstract

Host innate recognition triggers key immune responses for viral elimination. The sensing mechanism of hepatitis B virus (HBV), a DNA virus, and the subsequent downstream signaling events remain to be fully clarified. Here we found that type III but not type I interferons are predominantly induced in human primary hepatocytes in response to HBV infection, through retinoic acid-inducible gene-I (RIG-I)-mediated sensing of the 5'-ε region of HBV pregenomic RNA. In addition, RIG-I could also counteract the interaction of HBV polymerase (P protein) with the 5'-ε region in an RNA-binding dependent manner, which consistently suppressed viral replication. Liposome-mediated delivery and vector-based expression of this ε region-derived RNA in liver abolished the HBV replication in human hepatocyte-chimeric mice. These findings identify an innate-recognition mechanism by which RIG-I dually functions as an HBV sensor activating innate signaling and to counteract viral polymerase in human hepatocytes.

PMID:
25557055
DOI:
10.1016/j.immuni.2014.12.016
[Indexed for MEDLINE]
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