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Multi-Step Regulation of Interferon Induction by Hepatitis C Virus

Archivum Immunologiae et Therapiae Experimentalis volume 61, pages 127–138 (2013)Cite this article

Abstract

Acute hepatitis C virus (HCV) infection evokes several distinct innate immune responses in host, but the virus usually propagates by circumventing these responses. Although a replication intermediate double-stranded RNA is produced in infected cells, type I interferon (IFN) induction and immediate cell death are largely blocked in infected cells. In vitro studies suggested that type I and III IFNs are mainly produced in HCV-infected hepatocytes if the MAVS pathway is functional, and dysfunction of this pathway may lead to cellular permissiveness to HCV replication and production. Cellular immunity, including natural killer cell activation and antigen-specific CD8 T-cell proliferation, occurs following innate immune activation in response to HCV, but is often ineffective for eradication of HCV. Constitutive dsRNA stimulation differs in output from type I IFN therapy, which has been an authentic therapy for patients with HCV. Host innate immune responses to HCV RNA/proteins may be associated with progressive hepatic fibrosis and carcinogenesis once persistent HCV infection is established in opposition to the IFN system. Hence, innate RNA sensing exerts pivotal functions against HCV genome replication and host pathogenesis through modulation of the IFN system. Molecules participating in the RIG-I and Toll-like receptor 3 pathways are the main targets for HCV, disabling the anti-viral functions of these IFN-inducing molecules. We discuss the mechanisms that abolish type I and type III IFN production in HCV-infected cells, which may contribute to understanding the mechanism of virus persistence and resistance to the IFN therapy.

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Abbreviations

BMDC:

Bone marrow-derived dendritic cells

CTL:

Cytotoxic T lymphocytes

DAMP:

Damage-associated molecular pattern

DC:

Dendritic cell

dsRNA:

Double-stranded RNA

IFN:

Interferon

LD:

Lipid droplet

MAM:

Mitochondrial-associated endoplasmic reticulum membranes

MAVS:

Mitochondrial antiviral signaling protein

Mf:

Macrophages

mRNA:

Messenger RNA

NK:

Natural killer

NS:

Non-structural

RIG-I:

Retinoic acid-inducible gene I

RIP:

Receptor-interacting protein

STING:

Stimulator of IFN genes

TICAM-1:

Toll-IL-1-homology domain-containing adaptor molecule-1

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TNFR1:

TNF-α receptor 1

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Acknowledgments

We thank Drs. H. Takaki, M. Nakai, R. Takemura, S. Takahashi, L. C. Ring, A. Maruyama, J. Kasamatsu, H. Shime, and M. Azuma in our laboratory for their fruitful discussions. This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, and Culture (Specified Project for Advanced Research, MEXT) and the Ministry of Health, Labor, and Welfare of Japan, and by the Takeda and the Waxmann Foundations. Financial supports by a MEXT Grant-in-Project “the Carcinogenic Spiral”, “the National Cancer Center Research and Development Fund (23-A-44)”, and the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) are gratefully acknowledged.

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  1. Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita, Sapporo, 060-8638, Japan

    Hiroyuki Oshiumi, Kenji Funami, Hussein H. Aly, Misako Matsumoto & Tsukasa Seya

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  1. Hiroyuki Oshiumi
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  2. Kenji Funami
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  3. Hussein H. Aly
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  4. Misako Matsumoto
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  5. Tsukasa Seya
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Corresponding author

Correspondence to Tsukasa Seya.

Additional information

MAVS has been identified as the adaptor for RIG-I and MDA5 by four independent groups, and then also known as IPS-1, Cardif or VISA (Kawai and Akira 2009). TICAM-1 has been identified as the adaptor for TLR3 and TLR4 by two independent groups, and thus also described as TRIF (Oshiumi et al. 2003). In accordance with the HUGO Gene Nomenclature Committee-approved nomenclature, here we refer to these adaptor molecules as MAVS and TICAM-1, respectively.

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Oshiumi, H., Funami, K., Aly, H.H. et al. Multi-Step Regulation of Interferon Induction by Hepatitis C Virus. Arch. Immunol. Ther. Exp. 61, 127–138 (2013). https://doi.org/10.1007/s00005-012-0214-x

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Keywords

  • Hepatitis C virus
  • TLR3
  • TICAM-1 (TRIF)
  • MAVS (IPS-1, Cardif, VISA)
  • Interferon-inducing pathway
  • Double-stranded RNA