Deciphering the Origin and Evolution of Hepatitis B Viruses by Means of a Family of Non-enveloped Fish Viruses

Abstract

SummaryHepatitis B viruses (HBVs), which are enveloped viruses with reverse-transcribed DNA genomes, constitute the family Hepadnaviridae. An outstanding feature of HBVs is their streamlined genome organization with extensive gene overlap. Remarkably, the ∼1,100 bp open reading frame (ORF) encoding the envelope proteins is fully nested within the ORF of the viral replicase P. Here, we report the discovery of a diversified family of fish viruses, designated nackednaviruses, which lack the envelope protein gene, but otherwise exhibit key characteristics of HBVs including genome replication via protein-primed reverse-transcription and utilization of structurally related capsids. Phylogenetic reconstruction indicates that these two virus families separated more than 400 million years ago before the rise of tetrapods. We show that HBVs are of ancient origin, descending from non-enveloped progenitors in fishes. Their envelope protein gene emerged de novo, leading to a major transition in viral lifestyle, followed by co-evolution with their hosts over geologic eras.

Evolutionary biology of human hepatitis viruses

“…33 Endogenous and exogenous viruses distantly related to HBV were detected in reptiles, fish and amphibians. [34][35][36][37] HCV-related viruses were detected in horses in 2012, and evidence for sporadic spill-over infections of the horse-associated viruses into dogs and donkeys was found. [38][39][40][41] Soon afterwards, highly diverse HCV-related viruses were detected in bats and rodents, 42,43 in cattle, 44,45 and in black-and-white colobus monkeys.…”

“…29 In contrast, HBV-related viruses (henceforth, hepadnaviruses) are enveloped viruses, yet fish were recently found to host a non-enveloped Hepadnaviridae sister family, termed Nackednaviridae. 36 The discovery of nackednaviruses suggested that envelopment emerged de novo in hepadnaviruses capable of infecting mammals and ultimately humans. 36 A hallmark of HCV infection is the formation of lipoviral particles, which incorporate both host-derived lipoproteins and virus-derived glycoproteins.…”

“…36 The discovery of nackednaviruses suggested that envelopment emerged de novo in hepadnaviruses capable of infecting mammals and ultimately humans. 36 A hallmark of HCV infection is the formation of lipoviral particles, which incorporate both host-derived lipoproteins and virus-derived glycoproteins. 76 Interestingly, equine hepacivirus capsid proteins associate with intracellular lipid components, suggesting similarities between the replication of HCV and non-human HCV-related viruses (henceforth, hepaciviruses).…”

“…Indeed, similarities in the topologies of relatively old vertebrate lineages such as fish, amphibians and birds and their hepato-, hepadna-and hepaciviruses may hint at virus-host co-speciation. 36,203 In addition, evidence for co-speciation exists for the New World monkey hepadnaviruses CMHBV and WMHBV. 33 However, cross-species transmission must also have occurred during the evolution of hepatitis viruses.…”

“…While cross-species transmission may be relatively frequent in the enterically transmitted hepato-and hepeviruses, it seems to be comparably infrequent in bloodborne hepadna-and hepaciviruses. 29,36,205 Possible explanations for this observation include potentially easier transmission of highly stable enterically transmitted viruses compared to viruses likely transmitted exclusively through contact with body fluids. Additionally, different levels of host specificity due to receptor interactions or viral immune evasion strategies may play a role, as outlined earlier.…”