Evolutionary Analysis Provides Insight Into the Origin and Adaptation of HCV

Abstract

Hepatitis C virus (HCV) belongs to the Hepacivirus genus and is genetically heterogeneous, with seven major genotypes further divided into several recognized subtypes. HCV origin was previously dated in a range between ∼200 and 1000 years ago. Hepaciviruses have been identified in several domestic and wild mammals, the largest viral diversity being observed in bats and rodents. The closest relatives of HCV were found in horses/donkeys (equine hepaciviruses, EHV). However, the origin of HCV as a human pathogen is still an unsolved puzzle. Using a selection-informed evolutionary model, we show that the common ancestor of extant HCV genotypes existed at least 3000 years ago (CI: 3192–5221 years ago), with the oldest genotypes being endemic to Asia. EHV originated around 1100 CE (CI: 291–1640 CE). These time estimates exclude that EHV transmission was mainly sustained by widespread veterinary practices and suggest that HCV originated from a single zoonotic event with subsequent diversification in human populations. We also describe a number of biologically important sites in the major HCV genotypes that have been positively selected and indicate that drug resistance-associated variants are significantly enriched at positively selected sites. HCV exploits several cell-surface molecules for cell entry, but only two of these (CD81 and OCLN) determine the species-specificity of infection. Herein evolutionary analyses do not support a long-standing association between primates and hepaciviruses, and signals of positive selection at CD81 were only observed in Chiroptera. No evidence of selection was detected for OCLN in any mammalian order. These results shed light on the origin of HCV and provide a catalog of candidate genetic modulators of HCV phenotypic diversity.

Cross-order host switches of hepatitis C-related viruses illustrated by a novel hepacivirus from sloths

“…This was further substantiated by PamLX, in which the model allowing neutral/purifying selection was a better fit to the data (M8 (beta & ω) vs M7 (beta); log-likelihood scores: 1.2; df: 2; P = 0.5). In contrast to the preliminary study ( Forni et al. 2018 ), we found positive selection in rodent CD81 in two sites (S179 and N180) using FUBAR, and in five partially overlapping sites (N18, F21, N173, S179, I181) in MEME and of gene-wide episodic diversifying selection in BUSTED (P = 0.004) ( Supplementary Table S3 ).…”

“…2018 ). This hypothesis seems at odds with a preliminary study that analyzed selection signatures of CD81, CLDN1, OCLN, and SRB1 in different mammalian orders and found evidence for positive selection only in chiropteran, but not in rodent, CD81 ( Forni et al. 2018 ).…”

“…The accumulation of substitutions in the E1/E2 proteins was reminiscent of relatively higher variability of these regions within HCV ( Gray et al. 2011 ), likely associated with micro-evolutionary processes associated with host immune evasion ( Forni et al. 2018 ).…”

“…Since our evolutionary reconstructions suggest that rodents are major HV reservoirs, long evolutionary associations may have left signatures of positive selection in entry receptors ( Forni et al. 2018 ).…”

Evolutionary biology of human hepatitis viruses

“…For all human hepatitis viruses, projections of the most recent common ancestors (MRCA) based on extant viruses yield surprisingly similar results in the range of several thousand years before present. [183][184][185] Hypothetically, environmental factors such as the formation of large human populations, rearing of livestock and changes in land use might have contributed to the rise of hepatitis viruses in humans and explain the similarities of calculated MRCA. However, projections of ancient MRCA need to be treated with caution, because of the technical constraints of bioinformatic programmes, recombination events, and an inevitable sampling bias.…”