Experimental transmission of equine hepacivirus in horses as a model for hepatitis C virus

Abstract

Equine hepacivirus (EHCV; nonprimate hepacivirus) is a hepatotropic member of the Flaviviridae family that infects horses. Although EHCV is the closest known relative to hepatitis C virus (HCV), its complete replication kinetics in vivo have not been described, and direct evidence that it causes hepatitis has been lacking. In this study, we detected EHCV in 2 horses that developed post-transfusion hepatitis. Plasma and serum from these horses were used to experimentally transmit EHCV to 4 young adult Arabian horses, two 1-month-old foals (1 Arabian and 1 Arabian-pony cross), and 2 foals (1 Arabian and 1 Arabian-pony cross) with severe combined immunodeficiency (SCID). Our results demonstrated that EHCV had infection kinetics similar to HCV and that infection was associated with acute and chronic liver disease as measured by elevations of liver-specific enzymes and/or by histopathology. Although most of these animals were coinfected with equine pegivirus (EPgV), also a flavivirus, EPgV viral loads were much lower and often undetectable in both liver and blood. Three additional young adult Arabian-pony crosses and 1 SCID foal were then inoculated with plasma containing only EHCV, and evidence of mild hepatocellular damage was observed. The different levels of liver-specific enzyme elevation, hepatic inflammation, and duration of viremia observed during EHCV infection suggested that the magnitude and course of liver disease was mediated by the virus inoculum and/or by host factors, including breed, age, and adaptive immune status. Conclusion: This work documents the complete infection kinetics and liver pathology associated with acute and chronic EHCV infection in horses and further justifies it as a large animal model for HCV. (HEPATOLOGY 2015;61:1533-1546 H epatitis C virus (HCV), a member of the Hepacivirus genus in the family Flaviviridae, is estimated to persistently infect 150 million people throughout the world, and is a leading cause of cirrhosis and hepatocellular carcinoma. Development of a vaccine that prevents persistent infection is an important goal, but significant challenges to prophylaxis include viral immune escape, antigenic diversity of different viral strains, and the limitations of current mouse models for studies of HCV infection, progression, and vaccine development.1,2 Although humans are the only natural hosts for HCV, chimpanzees can be infected with HCV, develop similar clinical disease as humans, and currently represent the best model for vaccine studies.1 However, owing to the proposed listing of all chimpanzees as endangered and the resulting phase out of the use of chimpanzees in research, 3 alternative animal models are needed. Small animal models in which to dissect correlates of vaccine-mediated protection against HCV would have distinct advantages, but in their absence, alternative large animal models deserve consideration. Recent work has identified unique hepaciviruses and viruses of the closely related genus Pegivirus in rodents, bats, and

Immune protection against reinfection with nonprimate hepacivirus

“…We could confirm previously published data that horses can be experimentally infected by i.v. inoculation (23). All inoculated horses became viremic 1 wk postinfection and with the exception of one horse (horse 1) stayed viremic for several weeks.…”

“…An earlier study using immunedeficient foals indicated that disease outcome varies based on the development of the immune system. Normal immunocompetent foals and immune-deficient foals were not able to clear NPHV infection, whereas young adult horses did clear the virus (23). Future studies directly addressing intrahepatic immune responses could further clarify the roles of specific immune cells in viral clearance.…”

“…Similar to HCV, NPHV causes both acute and chronic infections in horses; although unlike HCV, the majority of animals are able to clear the infection (20)(21)(22). Experimental blood transmission has been shown, indicating that NPHV might be a blood-borne pathogen (23). Importantly, hepatotropism has been demonstrated for NPHV with viral replication occurring exclusively within the liver (20,22,23).…”

“…Experimental blood transmission has been shown, indicating that NPHV might be a blood-borne pathogen (23). Importantly, hepatotropism has been demonstrated for NPHV with viral replication occurring exclusively within the liver (20,22,23). Moreover, key viral evasion strategies are conserved between HCV and NPHV, as for instance, both viral proteases cleave their cognate innate immune adaptor protein MAVS (24,25).…”

Assessment of cross-species transmission of hepatitis C virus-related non-primate hepacivirus in a population of humans at high risk of exposure

“…As seen for another recently discovered horse virus, Theiler's diseaseassociated virus, which could be transmitted via inoculation of virus-containing serum products (Chandriani et al, 2013), a similar route of infection is likely for NPHV. Indeed, a recent study showed that NPHV could be transmitted experimentally between horses upon inoculation of NPHV-positive serum (Ramsay et al, 2015). It is Human sera of people with occupational horse contact (n5172) or people with no contact with horses (n5159) were screened for binding to NPHV NS3 or different NPHV E1E2 antigens (H10-H14) using the LIPS assay.…”