The Extraordinary Evolutionary History of the Reticuloendotheliosis Viruses

Abstract

Reticuloendotheliosis viruses are mammalian retroviruses that were transmitted to avian hosts through inadvertent human intervention, and subsequently integrated their genetic material into the genomes of large DNA viruses, generating novel recombinant pathogens that now circulate naturally in poultry and wild birds.

Abstract

The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruses isolated from birds. These viruses exhibit several highly unusual characteristics that have not so far been adequately explained, including their extremely close relationship to mammalian retroviruses, and their presence as endogenous sequences within the genomes of certain large DNA viruses. We present evidence for an iatrogenic origin of REVs that accounts for these phenomena. Firstly, we identify endogenous retroviral fossils in mammalian genomes that share a unique recombinant structure with REVs—unequivocally demonstrating that REVs derive directly from mammalian retroviruses. Secondly, through sequencing of archived REV isolates, we confirm that contaminated Plasmodium lophurae stocks have been the source of multiple REV outbreaks in experimentally infected birds. Finally, we show that both phylogenetic and historical evidence support a scenario wherein REVs originated as mammalian retroviruses that were accidentally introduced into avian hosts in the late 1930s, during experimental studies of P. lophurae, and subsequently integrated into the fowlpox virus (FWPV) and gallid herpesvirus type 2 (GHV-2) genomes, generating recombinant DNA viruses that now circulate in wild birds and poultry. Our findings provide a novel perspective on the origin and evolution of REV, and indicate that horizontal gene transfer between virus families can expand the impact of iatrogenic transmission events.

Author Summary

Retroviruses are characterized by their ability to insert a DNA copy of their genome into the chromosomes of infected cells. Occasionally, retroviruses insert into “germline” cells and are subsequently inherited as host alleles called endogenous retroviruses (ERVs). Vertebrate genomes contain thousands of ERV sequences derived from ancient retroviruses, and these viral sequences serve as molecular “fossils” that can be used to explore how retroviruses have evolved over millions of years. Here we combine an analysis of the retroviral “fossil record” with a phylogenetic and historical investigation to determine the origin of a group of avian retroviruses called reticuloendotheliosis viruses (REVs). We present evidence to demonstrate that rather than arising from natural infections of birds, REVs are in fact derived from mammalian retroviruses that were accidentally introduced into avian hosts during experimental studies of a malaria parasite in the late 1930s. Remarkably, REVs have subsequently inserted into the genomes of two large DNA viruses that infect birds, generating chimeric viruses that now circulate naturally in poultry and wild birds.