Highly Divergent Hepaciviruses from African Cattle

Abstract

The hepatitis C virus (HCV; genus Hepacivirus) is a highly relevant human pathogen. Unique hepaciviruses (HV) were discovered recently in animal hosts. The direct ancestor of HCV has not been found, but the genetically most closely related animal HVs exist in horses. To investigate whether other peridomestic animals also carry HVs, we analyzed sera from Ghanaian cattle for HVs by reverse transcription-PCR (RT-PCR). Nine of 106 specimens from different sampling sites contained HV RNA (8.5%) at median viral loads of 1.6 ؋ 10 5 copies/ml. Infection seemed unrelated to cattle age and gender. Near-full-genome sequencing of five representative viruses confirmed taxonomic classifications. Cattle HVs formed two distinct phylogenetic lineages that differed by up to 17.7% on the nucleotide level in the polyprotein-encoding region, suggesting cocirculation of different virus subtypes. A conserved microRNA122-binding site in the 5= internal ribosomal entry site suggested liver tropism of cattle HVs. Phylogenetic analyses suggested the circulation of HVs in cattle for several centuries. Cattle HVs were genetically highly divergent from all other HVs, including HCV. HVs from genetically related equine and bovine hosts were not monophyletic, corroborating host shifts during the evolution of the genus Hepacivirus. Similar to equine HVs, the genetic diversity of cattle HVs was low compared to that of HCV genotypes. This suggests an influence of the human-modified ecology of peridomestic animals on virus diversity. Further studies should investigate the occurrence of cattle HVs in other geographic areas and breeds, virus pathogenicity in cattle, and the potential exposure of human risk groups, such as farmers, butchers, and abattoir workers. IMPORTANCEHCV (genus Hepacivirus) is a major human pathogen, causing liver failure and cancer. Unique hepaciviruses (HVs) were discovered over the last few years in animals, but the direct ancestor of HCV has not been found. The animal HV most closely related to HCV so far originated from horses, suggesting that other livestock animals also harbor HVs. Therefore, we investigated African cattle and discovered previously unknown HVs at high prevalence and viral loads. Because of the agricultural importance of cattle, it may be relevant to investigate HV pathogenicity. The frequent exposure of humans to cattle also may warrant investigations of the zoonotic potential of these viruses. Evolutionary analyses suggested that cattle HVs have existed for centuries. Despite the genetic relatedness of their animal hosts, HVs from cattle and horses were not phylogenetically related, corroborating frequent host shifts during the evolution of the genus Hepacivirus.

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

“…The observation of viral admixture in equids is paralleled by the occurrence of closely related HVs in cattle in Ghana and Germany (12,44). Probably, the distribution of cattle has undergone anthropogenic change in an extent similar to that of equids.…”

“…A short evolutionary association between equine hosts and EqHV is also consistent with the highly diverse HV lineages found in the genetically related hosts belonging to the order Artiodactyla (cattle). The perissodactylan and artiodactylan lineages clearly did not cospeciate with their hosts (12), and whether both of them are the result of independent cross-species HV transmission events or whether unique host associations can be found for either the perissodactylan or the artiodactylan lineage remains to be determined. Immediate experimental approaches include testing of related host species, e.g., zebras for the Perissodactyla and livestock species like sheep or goats for the Artiodactyla.…”

“…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 lack of cosegregation of HVs with mutually related animal hosts, as well as the detection of potential recombination events between some HV lineages, suggest low barriers against cross-host transmission (10)(11)(12)(13). However, whether any of the animal species known to carry HVs represents a direct reservoir for HCV is unclear (14).…”

Discovery of a Novel Human Pegivirus in Blood Associated with Hepatitis C Virus Co-Infection

“…Our report of at least 12 strains of HPgV-2 infecting humans is consistent this pattern, with each strain sharing~94% identity to one another. Over 80 novel hepaciviruses and pegviruses have now been reported in bats [13], as well as multiple novel hepaciviruses in rodents [9], cattle [8] and horses [7,10,12], underscoring the extraordinary diversity of these viruses in animal reservoirs. Thus, whether HPgV-2 arose early in the evolutionary history of pegiviruses or is the result of a more recent zoonotic spillover event from a mammalian reservoir remains to be established.…”

“…Novel animal hepaciviruses and pegiviruses have previously been found in multiple animal reservoirs, including bats, rodents, cows, and horses [7][8][9][10][11][12][13]. While hepaciviruses such as HCV in humans and GBV-B are established hepatitis agents [14], traditional criteria for classification of viruses as pegiviruses have included phylogenetic relatedness, persistent infection in the host and, importantly, apparent lack of pathogenicity [15,16].…”