Identification of a receptor for an extinct virus – now that's clever

Retrovirus Scientists are studying a retrovirus that has been dormant in chimpanzees and their ancestors for at least one million years. The virus, known as CERV2, is present in the genomes of chimpanzees, but not those of humans, suggesting that chimpanzees’ ancestors became infected after they diverged from human ancestors 5–6 million years ago. The virus was clearly replicating around the time that the first humans were trotting around Africa and beginning to think about colonizing the rest of the world. As a receptor, the ancient virus exploited a transport protein that normally transports copper into and out of cells.

Identification of a receptor for an extinct virus. PNAS USA October 25, 2010 doi: 10.1073/pnas.101234410
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 CuCl2 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 copper-coordinating residues, and this may represent an evolutionary barrier to the acquisition of CERV2 resistance in primates.

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