Identification of a receptor for an extinct virus

Abstract

The resurrection of endogenous retroviruses from inactive molecular fossils has allowed the investigation of interactions between extinct pathogens and their hosts that occurred millions of years ago. Two such paleoviruses, chimpanzee endogenous retrovirus-1 and -2 (CERV1 and CERV2), are relatives of modern MLVs and are found in the genomes of a variety of Old World primates, but are absent from the human genome. No extant CERV1 and -2 proviruses are known to encode functional proteins. To investigate the host range restriction of these viruses, we attempted to reconstruct functional envelopes by generating consensus genes and proteins. CERV1 and -2 enveloped MLV particles infected cell lines from a range of mammalian species. Using CERV2 Env-pseudotyped MLV reporters, we identified copper transport protein 1 (CTR1) as a receptor that was presumably used by CERV2 during its ancient exogenous replication in primates. Expression of human CTR1 was sufficient to confer CERV2 permissiveness on otherwise resistant hamster cells, and CTR1 knockdown or CuCl 2 treatment specifically inhibited CERV2 infection of human cells. Mutations in highly conserved CTR1 residues that have rendered hamster cells resistant to CERV2 include a unique deletion in a copper-binding motif. These CERV2 receptor-inactivating mutations in hamster CTR1 are accompanied by apparently compensating changes, including an increased number of extracellular coppercoordinating residues, and this may represent an evolutionary barrier to the acquisition of CERV2 resistance in primates.endogenous retrovirus | copper transport T he ability of retroviruses to integrate into the genomes of target cells allows for the possibility of Mendelian inheritance of proviruses if integration into the host germ line occurs (1). This route of transmission results in an organism-wide presence of provirus in the genomes of progeny. Such endogenization events have occurred numerous times during primate evolution and many proviruses have become fixed in host populations (2-5). Endogenous retroviruses thus represent a record of ancient infections and these "paleoviruses" can provide information about the evolution of host-virus interactions (6, 7).Endogenous γ-retroviruses are abundant in primate genomes and among them, chimpanzee endogenous retroviruses-1 and -2 (CERV1 and CERV2) and their relatives are the groups most closely related to the modern prototype γ-retrovirus, MLV (3, 4). CERV1 and -2 are assumed to be extinct, although without exhaustive sampling, it is nearly impossible to definitively demonstrate that intact exogenous relatives are not currently replicating in some modern primate species. They are of particular interest because of their peculiar absence from the human genome, although homologs exist in the genomes of chimpanzee, bonobo, gorilla, and Old World monkeys. Thus, both viruses apparently replicated after the divergence of the human and chimpanzee lineages approximately 6 million years ago, with zoonoses ultimately resulting in endogenization in diver...

Pushing the endogenous envelope

“…In the primate lineage, HERV-K(HML5) is estimated to have infected our ancestors some 55 Ma [55], and also carries a beta-type TM, suggesting a long association with mammals of retroviruses with non-covalently associated Env subunits [26]. Similarly, many examples of gamma-type TM sequences can be found among ERVs estimated to have been infectious tens of millions of years ago, such as an ERV of Bos taurus , BoERV1, that is estimated to have integrated into the germline of the ancestors of cattle between 58 and 126 Ma [56]; and the chimpanzee ERV, CERV1, estimated to have integrated as long ago as 82 Myr [57]. …”

Seasonal Effects on Great Ape Health: A Case Study of Wild Chimpanzees and Western Gorillas

“…Given their phylogenetic relatedness, wild populations of non-human primates are an indicator species for monitoring emerging pathogens, providing crucial information on infectious diseases that may also affect humans (e.g. [1], [3]–[11]). …”

Host Genes Important to HIV Replication and Evolution

“…A second example of reconstruction, this time of 20-million-year-old TRIM5a, suggested that restriction of HIV-1 has decreased during evolution leading to humans (Goldschmidt et al 2008). Soll et al investigated two chimpanzee endogenous retrovirus-1 and -2 (CERV1 and CERV2) relatives of modern murine leukemia viruses (MLVs) that are present in the genomes of Old World primates, but absent from the human genome (Soll et al 2010). Using CERV2 Env-pseudotyped MLV vectors, Soll et al identified copper transport protein 1 (CTR1) as a receptor that was presumably used by CERV2 during its ancient exogenous replication in primates.…”