Did hepatitis C virus originate in horses?

Dog and horseAbout 2% of the world’s population is chronically infected with hepatitis C virus (HCV). This enveloped, positive-strand RNA virus was discovered in 1989, but serological and phylogenetic evidence indicates that it has been infecting humans for hundreds of years, perhaps as long ago as the 14th century. All human viral infections most likely originated in non-human species, but the progenitor of HCV is not known. Recent evidence suggests that horses might have been the source of HCV in humans.

For many years there were no known non-human relatives of HCV until canine hepacivirus was discovered in dogs (we discussed this virus on TWiV #137). However two subsequent studies failed to reveal additional evidence for CHV infection of dogs. In one study, no antibodies to CHV were found in sera from 80 dogs in New York State, and in a second study, PCR failed to detect CHV nucleic acid sequences in 190 samples from dogs in Scotland. Samples from rabbits, deer, cows, cats, mice, and pigs were also negative for CHV. However both groups found evidence for infection of horses. These viruses have been called non-primate hepaciviruses (NPHV).

In one study carried out on horses in New York State, 8 of 103 samples were found to contain antibodies to NPHV. Complete viral genomes were identified from all 8 horses. Most are genetically distinct from CHV, but one viral sequence, obtained from a pool of sera from New Zealand horses, is nearly identical to CHV. NPHV was also detected by PCR in sera from 3 of 175 Scottish horses. Separate serum samples obtained from one horse 5 months apart were positive for viral RNA, indicating persistent infection. None of the horses had any evidence of clinical hepatitis or any other illness.

These results from geographically distinct areas suggest that horses are a reservoir of NPHV. It seems likely that dogs might acquire NPHV infection from horses, as there are opportunities for contact between the two animals on farms or in kennels. Additional NPHV isolates from horses must be studied to confirm this hypothesis.

It will be important to determine if horse NPHV was the source of human HCV. This is theoretically possible because horse products, such as serum containing antibodies to pathogens or toxins, have been injected into humans. There are six genotypes of HCV, each of which is believed to have emerged at different times and geographic locations. Whether their emergence represent different cross-species transmissions, as is the case with the different groups of HIV-1, remains to be determined.

I also wonder how horses originally acquired NPHV. Perhaps it was transmitted to them from another species via a vector bite, such as a mosquito – but from what species?

TWiV 137: Look what the dog dragged in

dog_humanHosts: Vincent Racaniello, Alan Dove, Rich Condit, Dickson Despommier, Amit Kapoor, and Ian Lipkin

The TWiV team speaks with Amit Kapoor and Ian Lipkin about how they discovered canine hepacivirus, and its implications for the origin and evolution of hepatitis C virus.

Click the arrow above to play, or right-click to download TWiV #137 (69 MB .mp3, 96 minutes).

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Canine hepacivirus, a relative of hepatitis C virus

yellow labradorContemporary human viruses most likely originated by cross-species transmission from non-human animals. Examples include HIV-1, which crossed from chimpanzees to humans, and SARS coronavirus, which originated in bats. Since the 1989 discovery of hepatitis C virus (classified as a hepacivirus in the family Flaviviridae) the origin of the virus been obscure. During the characterization of respiratory infections of domestic dogs, a virus was discovered that is the most genetically similar animal virus homolog of HCV.

HCV is a substantial human pathogen: 200 million people worldwide are chronically infected and are at risk for the development of hepatocellular carcinoma. The source of HCV is unknown because there are no closely related animal virus homologs, but the hunt for related viruses has focused mainly on nonhuman primates. The identification of a related virus was fortuitous, and came about during a study of respiratory viruses that infect dogs. Nasal swabs were obtained from dogs with respiratory illness in shelters in Texas, Utah, and Pennsylvania. Sequence analysis of viral nucleic acids revealed the presence of a virus related to HCV, which was named canine hepacivirus (CHV). The virus was found in respiratory samples from 6 of 9 and 3 of 5 dogs in two separate outbreaks of respiratory disease, but not in 60 healthy pet dogs.

CHV was present in liver, but not lung, of 5 dogs that had died from unexplained gastrointestinal illness. The amount of CHV RNA in respiratory samples was substantially higher than in liver. Viral RNA was detected in the cytoplasm of hepatocytes in canine liver, but whether CHV is hepatotropic (replicates in liver cells) in dogs is not known. In humans, the amount of HCV in respiratory samples is typically very low. CHV may therefore infect different cells and tissues in dogs than does HCV in humans.

Bioinformatic analysis of CHV revealed that it is the genetically more related to HCV than any other known virus. HCV and CHV probably shared a common ancestor that circulated between 500 and 1,000 years ago – many years after dogs were domesticated. It is possible that hepaciviruses are mainly dog viruses, and that HCV arose by transmission of the virus from a dog to a human. An alternative scenario that cannot be excluded is that hepaciviruses infect many animal species. Screening of other animals for the presence of hepaciviruses must be done to determine which hypothesis is correct.

It was not possible to infect canine cultured cells with CHV, using clinical specimens from dogs.  The reason for this failure is not known, but could mean that the cells used are not susceptible and/or permissive for viral replication. Furthermore, a full-length DNA copy of the viral genome, which could be used to produce infectious viral RNA, was not reported. Propagation of the virus in cell cultures will be essential for enabling research on CHV replication and pathogenesis.

The discovery of CHV is exciting because the virus provides clues about the origins of HCV and will likely stimulate a search for related viruses in other animals. It is possible that CHV infection of dogs might be a model for understanding the pathogenesis of HCV, which currently is only possible in chimpanzees. A convenient animal model would be valuable for devising new ways to prevent and treat HCV infections.

A. Kapoor, P. Simmonds, G. Gerold, N. Qaisar, K. Jain, J.A. Henriquez, C. Firth, D.L. Hirschberg, C. Rice, S. Shields, & W.I. Lipkin. (2011). Characterization of a canine homolog of hepatitis C virus Proc. Natl. Acad. Sci. USA