Did hepatitis C virus originate in horses?

12 February 2013

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?

  • http://twitter.com/cggbamford Connor Bamford

    In light of recent European qualms over horse meat contamination in processed meats, could this be a means of cross species transmission?

  • Junio C Hamano

    This is most likely an off-topic, but “All human viral infections most likely originated in non-human species” caught my eyes and piqued my curiosity.

    What would be the scientific method to substantiate or refute such a conjecture?

    For each and every virus species that infect human, see if their relatives appear in non-human species and determine that theirs is older in ancestry relationship than ours? I would imagine that such a study can never be exhaustive, so probably you have to stop at some point with “OK, we’ve seen enough; everything we studied so far is of non-human origin and it is likely all the rest are.” Perhaps there are more rigorous method scientists used to reach that conclusion?

    If similar studies were done for the originating hosts of human viruses, I wonder where such studies would lead to. Perhaps X% of human viruses turns out to have come from non-human primates, and all of them originally infected non-primates (say, Y% of that X% was from mice). Digging further, scientists may find out that all murine viruses have come from other species. If we go on and on, will we find the very original host for all viruses? If such a discovery were to be made, what would the significance of such a finding be?

    Or maybe we would find some circular dependencies somewhere in the chain?

  • Brandt Levitt

    Surprising. I assumed that human hepacivirus came from particularly error-prone clones of other flaviviruses and was introduced into humans by the bite of a mosquito. The idea that perhaps the human hepacivirus evolved from a horse equivalent injected into humans in the form of serum is quite interesting. It squares with the observation that there aren’t other human hepaciviruses and the relatively recent emergence of Hep C. However, the canine version of the envelope protein, E2, is most similar to the human version, despite being the most variable region of the viral genome. This suggests that maybe our version of HCV came from dogs. Cool stuff.

  • http://www.virology.ws profvrr

    I think it is unlikely that HCV can be acquired by eating contaminated food – the virus particles are unlikely to survive the extremes of the intestinal tract. Injecting people with horse serum is a more likely route.

  • Brandt Levitt

    What would be the scientific method to substantiate or refute such a conjecture?

    Molecular clock analyses. dN/dS calculations. homology searches.

    but you’re correct that this can never be exhaustive. Frankly I find it amazing that any viruses entered humans from non primates.

  • http://www.virology.ws profvrr

    Not off topic at all. Very interesting problem. I wrote ‘most likely’ because we can never prove otherwise, but I suspect that all of our current human viruses originated in animals. I believe that most of the existing kinds of viruses evolved a long time ago, long before humans emerged. When Homo sapiens came on the scene, it picked up viruses from other animals, and we have been doing so since. In support of this idea, molecular clock analyses date many viruses to millions of years ago (but such analyses have only been done for less than a dozen viruses).

    Many of our current human pathogenic viruses, we can find likely ancestors in animals. Influenza virus, measles virus, HIV-1 and HIV-2. We don’t know where others came from (e.g. poliovirus) but that’s probably because we have not looked hard enough. It is a problem worthy of study because it will give clues about how viruses change species.

    How far back can you go? Probably a long way. Humans acquired HIV-1 from chimpanzees in the form of SIV; chimpanzees in turn acquired SIV from Old World monkeys. They may have had the virus for millions of years, but who knows where it began?

    Viruses probably first evolved with the first cells – that’s a long time ago. As new multicellular life arose, then advanced, the viruses went with them. If only I could travel back in time and take samples!

  • http://www.virology.ws profvrr

    It’s thought that smallpox arose from a gerbil poxvirus !

  • Andrew Rambaut

    Interesting but the horse virus diversity is separate from and less than that of human HCV (see phylogeny from the Burbelo paper, below). I can see no reason to state that the origin of the human lineage is from horses (or dogs, for that matter – see Peter Simmonds paper). It is equally parsimonious that both species got it from some other reservoir, perhaps on the same timescale of recent (geologically, speaking) human history. Or that an more ancient human lineage jumped into horses since domestication. My speculation would be that HCV evolved from a GBV-C like virus which was endemic in primates and largely vertically transmitted.

  • Andrew Rambaut

    Tree didn’t upload – trying again…

  • Andrew Rambaut

    I think injecting horse serum is unlikely source of HCV – the individual HCV genotypes are at least hundred of years old [http://vir.sgmjournals.org/content/90/9/2086]. When you combine this with the phylogeny (two mutually monophyletic groups – HCV and NPHV) it suggests a single origin of human HCV hundreds or thousands of years ago. If a relatively recent transmission from horses was the source of HCV (or multiple sources of individual genotypes) then we would expect the HCV lineages to be nested within the NPHV diversity in the tree.

  • Joe Grove

    Although it seems likely that humans acquired the majority of current viruses from animal reservoirs, your discussion seems to treat humans as distinct from animals. It’s not as if we appeared on day zero as a completely infection naive species. Some viruses may be baggage that we’ve been carrying since we last shared an ancestor with non-human primates?