Abstract

Canine hepacivirus (CHV) was recently identified in domestic dogs and horses. The finding that CHV is genetically the virus most closely related to hepatitis C virus (HCV) has raised the question of whether HCV might have evolved as the result of close contact between dogs and/or horses and humans. The aim of this study was to investigate whether the NS3/4A serine protease of CHV specifically cleaves human mitochondrial antiviral signaling protein (MAVS) and Toll-IL-1 receptor domain-containing adaptor inducing interferon-beta (TRIF). The proteolytic activity of CHV NS3/4A was evaluated using a bacteriophage lambda genetic screen. Human MAVS- and TRIF-specific cleavage sites were engineered into the lambda cI repressor. Upon infection of Escherichia coli cells coexpressing these repressors and a CHV NS3/4A construct, lambda phage replicated up to 2000-fold more efficiently than in cells expressing a CHV protease variant carrying the inactivating substitution S139A. Comparable results were obtained when several HCV NS3/4A constructs of genotype 1b were assayed. This indicates that CHV can disrupt the human innate antiviral defense signaling pathway and suggests a possible evolutionary relationship between CHV and HCV.

Highlights

  • The origin of hepatitis C virus (HCV) infections in humans has remained unknown, because related animal virus homologs had not been identified [1,2]

  • We previously demonstrated that the bacteriophage lambda–based genetic screen employed here can be used to characterize site-specific proteases, including HCV NS3/4A, human immunodeficiency virus (HIV), and respiratory syndrome (SARS) coronavirus proteases [17,18,19,20,21,22, 23,24]

  • Adaptation of canine hepacivirus (CHV) and NPHV to human cells would likely require these viruses to evade the human cellular innate immune response, which responds to viral pathogens by RNA composition–dependent activation of retinoic acid inducible gene-I (RIG-I) and subsequent signalling via interferon regulatory factor (IRF)-3 [6]

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Summary

Introduction

The origin of hepatitis C virus (HCV) infections in humans has remained unknown, because related animal virus homologs had not been identified [1,2]. A Flaviviridae RNA genome that was isolated from domestic dogs with respiratory illness was found to be the virus most closely related to HCV [3]. This Flaviviridae agent is known as canine hepacivirus (CHV). The discovery of CHV may shed light on the origin of HCV, and may serve as a new model system with which to study this deadly human virus. The discovery of the close homology between CHV and HCV is intriguing, there are barriers preventing viral transmission across species. Cross-species transmission of CHV to humans would most likely require evasion of the human cellular innate immune response, which leads to type I interferon production through RNA composition–dependent activation of retinoic acid inducible gene-I (RIG-I) and toll-like receptor (TLR) [6]

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