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Volume 97, Issue 11

Hepatitis C virus replicative double-stranded RNA is a potent interferon inducer that triggers interferon production through MDA5 Free

Abstract

The cytoplasmic RNA sensors, retinoic acid-inducible gene I and melanoma differentiation-associated gene 5, play crucial roles in innate sensing of hepatitis C virus (HCV). However, the exact identity of the IFN inducer generated during HCV infection is poorly understood. To identify the IFN inducer, we extracted the RNAs from HCV-replicating cells and introduced these into IFN signalling-competent cells to examine IFN production. RNAs isolated from HCV-replicating cells triggered robust IFN-β and IFN-λ production in Huh7 cells in a viral replication-dependent manner, preferentially through the melanoma differentiation-associated gene 5 but not through the retinoic acid-inducible gene I-mediated pathway. The IFN-inducing capacity of HCV RNA survived after calf intestinal alkaline phosphatase and ssRNA-specific S1 nuclease treatment, but was completely eliminated by dsRNA-specific RNase III digestion, suggesting that viral replicative dsRNA is an IFN inducer. Furthermore, HCV viral RNA extracted from replicating cells was sensitive to 5′-monophosphate-dependent 5′→3′ exonuclease (TER) digestion, suggesting that the HCV genome lacks a 5′-triphosphate or -diphosphate. In semi-permeabilized cells, the HCV IFN inducer primarily resided in an enclosed membranous structure that protects the IFN inducer from RNase digestion. Taken together, we identified HCV replicative dsRNA as a viral IFN inducer enclosed within the viral replication factory.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): HCV , innate immunity , interferon , MDA5 , replication complex and RIG-I
© 2016 The Authors
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2016-11-10
2024-04-19
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Hepatitis C virus replicative double-stranded RNA is a potent interferon inducer that triggers interferon production through MDA5
J. Gen. Virol. 97, 2868 (2016); https://doi.org/10.1099/jgv.0.000607
/content/journal/jgv/10.1099/jgv.0.000607
/content/journal/jgv/10.1099/jgv.0.000607
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