Surveying the global virome: Identification and characterization of HCV-related animal hepaciviruses

Abstract

Recent advances in sequencing technologies have greatly enhanced our abilities to identify novel microbial sequences. Thus, our understanding of the global virome and the virome of specific host species in particular is rapidly expanding. Identification of animal viruses is important for understanding animal disease, the origin and evolution of human viruses, as well as zoonotic reservoirs for emerging infections. Although the human hepacivirus, hepatitis C virus (HCV), was identified 25 years ago, its origin has remained elusive. In 2011, the first HCV homolog was reported in dogs but subsequent studies showed the virus to be widely distributed in horses. This indicated a wider hepacivirus host range and paved the way for identification of rodent, bat and non-human primate hepaciviruses. The equine non-primate hepacivirus (NPHV) remains the closest relative of HCV and is so far the best characterized. Identification and characterization of novel hepaciviruses may in addition lead to development of tractable animal models to study HCV persistence, immune responses and pathogenesis. This could be particular important, given the current shortage of immunocompetent models for robust HCV infection. Much remains to be learned on the novel hepaciviruses, including their association with disease, and thereby how relevant they will become as HCV model systems and for studies of animal disease. This review discusses how virome analysis led to identification of novel hepaci- and pegiviruses, their genetic relationship and characterization and the potential use of animal hepaciviruses as models to study hepaciviral infection, immunity and pathogenesis. This article forms part of a symposium in Antiviral Research on “Hepatitis C: Next steps toward global eradication.”

Differential Infection Patterns and Recent Evolutionary Origins of Equine Hepaciviruses in Donkeys

“…Furthermore, the detection of viral RNA at comparable loads in the French sera sampled in 1979 and Bulgarian sera sampled in 2015 implicated suitability of the non-recently sampled specimens for viral RNA detection. Viral clearance is typically delayed in HV infection, including infection with EqHV in horses (7). In our study, three serial individual specimens taken at different time points over 2 weeks (May-June 1979) were available from the RNA-positive donkey sampled in France.…”

“…The evolutionary origins of HCV have remained obscure (6). Recent studies identified numerous hepaciviruses (HVs) in bats, rodents, monkeys, and peridomestic animals (7,8). Considering the absence of HCV-related viruses in higher primates (9), as well as the existence of genetically diversified nonprimate HVs, mammals other than primates may have shaped primordial HCV evolution (10).…”

“…The equine HV (EqHV; originally described as canine HV and subsequently as nonprimate HV) (7,8), constitutes the closest animal-associated relative of HCV among the HVs known so far (7,13). Sporadic infections of dogs (15)(16)(17) support a broad host range of EqHV that may have enabled infection of humans with EqHV in the past.…”

Characterization of nonprimate hepacivirus and construction of a functional molecular clone

“…Searches for related viruses in primates were unsuccessful, leaving the history and origin of HCV unknown. Recently, developments in deep sequencing methods accelerated identification of a number of related viruses (1). Nonprimate hepacivirus (NPHV) was the first to be discovered, initially identified in samples from dogs and termed canine hepacivirus (2).…”

Ion Channel Function and Cross-Species Determinants in Viral Assembly of Nonprimate Hepacivirus p7

“…Recently, multiple new hepaciviruses have been identified in dogs (1), horses (2), bats (3,4), rodents (3,5), nonhuman primates (6), rats (7), and cattle (8,9). Among them, nonprimate hepacivirus (NPHV), initially described to infect dogs and subsequently horses, is the closest homolog of HCV and thus represents a unique model to study differences in hepacivirus pathogenesis of HCV and HCV-related viruses (10,11).…”