Hepatitis C homolog in dogs with respiratory illness.

I n PNAS, Kapoor et al. (1) discover a Flaviviridae agent most closely related to hepatitis C virus (HCV); the identified RNA genome was isolated from domestic dogs with respiratory illness. This might shed new light on the origin and evolution of HCV and could lead to surrogate model systems for this important human pathogen. Over 100 million people are affected by hepatitis C worldwide, but research has been hampered by a lack of widely available animal models and representative culture systems. Thus, discovery of an HCV homolog in dogs gives hope for finding new ways to study this deadly human virus. The host range of HCV is restricted, and natural infection was detected only in humans; higher primates are susceptible to experimental infection (Fig. 1). However, an HCV homolog has not been detected in higher primates to date. The only other known homolog is GB virus B (GBV-B), which causes hepatitis in experimentally infected New World monkeys, but its true origin remains unknown (2) (Fig. 1). Thus, the finding of a homolog in dogs raises the interesting proposition that HCV might have evolved as a result of the close contact between dogs and humans during the past several thousand years. Kapoor et al. (1) estimate a divergence time of the dog and human viruses from a common ancestor within the past 500–1,000 y, but it is widely recognized that such calculations should be interpreted with great caution. As pointed out by Kapoor et al. (1), a relatively recent zoonotic origin of HCV would fit well with the high pathogenic potential of HCV in humans. However, it will be of interest to determine whether there are further HCV homologs in other mammals. They could be a widespread group of hostspecific viruses causing little or no disease, as observed for a more distantly related cluster of Flaviviridae (suggested genus Pegivirus), GBV-A and GBV-C viruses, in primates and humans (2–5). The International Committee of Taxonomy of Viruses deals with classification of viruses in a formalized way after researchers submit suggestions. Kapoor et al. (1) call the HCV homolog isolated from dogs canine hepacivirus (CHV). Based on analysis of the evolutionary conserved helicase and RNA polymerase regions of members of the different genera of Flaviviridae, it is apparent that the genome sequence of CHV clusters with HCV and GBV-B. HCV is the sole recognized species member of the genus Hepacivirus; GBV-B is a suggested species. Based on a detailed phylogenetic analysis, Kapoor et al. (1) suggest that CHV should be classified as a uniqueHepacivirus species. However, HCV and GBV-B are hepatotropic, and it is not clear whether that is the case for CHV (Fig. 1). Also, although CHV was detected in dogs from different outbreaks of respiratory disease, it should be confirmed that this is a canine virus. Given the heterogeneity of HCV, it was surprising that CHV sequences recovered from respiratory or liver samples from dogs in different outbreaks were practically identical. These researchers screened a number of healthy dogs and did not detect CHV. Additional studies will be required to confirm the canine origin of this virus. It would be relevant to develop a specific serological test to screen dogs and other animals to determine how widespread infections with CHV are. The study by Kapoor et al. (1) is limited to a detailed analysis of the near-complete genome of CHV. Given the close relatedness to HCV, such data are of particular interest during a time when new sequence-independent amplification and sequencing technologies, also applied here, will result in detection of numerous new viruses, which may or may not have any disease relevance. The challenge will be to determine whether such unique viruses, including CHV, cause disease in the host where they were discovered or in other susceptible animals. Questions about virulence and pathogenesis and, as mentioned above, the epidemiology of this virus are important to address. The CHV genome was found at a high titer in respiratory samples from sick dogs, and the virus was not detected in healthy dogs (Fig. 1). This would suggest that CHV played a role in the respiratory illness observed in these particular dogs. It will, however, be important to perform animal transmission studies using serial dilutions of high-titer virus stocks to demonstrate that CHV is a transmissible agent that causes respiratory illness. This would begin to address Koch’s postulate for a disease-causing agent. Other disease outbreaks in dogs around the world should be examined. At present, there are no definitive data on target organs or disease association of this virus. How is it transmitted to other dogs? Does it infect other mammals? It would be of interest to determine whether different variants of CHV exist as observed for HCV with diverse major genotypes. Fig. 1. Prototype HCV species and suggested species within the genus Hepacivirus of the Flaviviridae family of viruses and their natural and experimental hosts. The p13 protein of GBV-B might be processed into a p7 protein (equivalent to HCV p7) and a p6 protein. The p6 protein is not required for in vivo infectivity (8). The tamarin from which GBV-B was isolated had been inoculated with the GB-agent (2). Persistent infection has been reported with recombinant GBV-B (8).