Editors' ChoiceInfectious Disease

HCV Homolog in Dog: A Scientist’s Best Friend

Science Translational Medicine  29 Jun 2011:
Vol. 3, Issue 89, pp. 89ec100
DOI: 10.1126/scitranslmed.3002800

Abstract

The dog days of summer have finally arrived—for scientists who study human hepatitis C virus (HCV); these researchers have long been limited by the lack of a small-animal model for HCV infection. Now, Kapoor et al. have discovered canine Hepacivirus (CHV), the closest genetically similar HCV homolog identified to date. The new virus makes possible the development of a nonprimate animal model of viral persistence that can be used for testing vaccine efficacy and therapeutic drug discovery.

HCV chronically infects 3% of the global population, and nearly 80% of people who contract an acute HCV infection develop chronic viral hepatitis with subsequent risk of cirrhosis and liver cancer. Although HCV was first identified in the late 1980s, a vaccine has remained elusive; one reason is the lack of a closely related animal virus homolog that would enable study of the virus in its native state in a model system. In a study focused on the viral flora found in companion animals, Kapoor et al. found a previously unidentified hepacivirus (CHV). Nasal swabs were isolated from sick shelter dogs during a respiratory infection outbreak and used to recover RNA viruses. The viral genomes were amplified, sequenced, and compared with known viral genome sequences by using BLAST analysis. Analyzing 6500 continuous nucleotides, the authors demonstrated a unique viral sequence (CHV) with a surprisingly close homology to HCV. To validate their findings, the authors performed similar experiments on nasal swabs from an additional 33 dogs that had become ill during five separate respiratory outbreaks and demonstrated a high degree of genetic relatedness to CHV among viruses isolated from the infected animals. Samples from healthy animals did not show the presence of CHV. Comparison of the putative CHV genome cleavage map for structural and nonstructural proteins with that of HCV revealed a similar number of predicted polyproteins with intriguing homology in the envelope protein domain (E2), a feature not found in the hitherto closest known viral relative of HCV (GBV-B).

For an animal model of HCV disease to be of use in therapeutics discovery, it must display persistent infection; to do so, CHV needs to have the proper associated viral apparatus to cause persistent infection, similar to that found in HCV. The investigators used a predictive model (MFOLD) to show that CHV genome RNAs encode GORS (genome-scale ordered RNA structure), a stable secondary structure found in persistent HCV infection. Kapoor and colleagues speculate that HCV arose from a zoonotic source (CHV), which would explain the degree of pathogenicity in humans and the difficulty in propagation via an oral or inhaled route. Before CHV can be used as a model for HCV, additional studies must determine whether CHV, like HCV, infects the liver and whether any of the few genomic differences between HCV and CHV are biologically important.

A. Kapoor et al., Characterization of a canine homolog of hepatitis C virus. Proc. Natl. Acad. Sci. U.S.A. 24 May 2011 (10.1073/pnas.1101794108). [Abstract]