MicrobiologyBytes

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.

Related:

• Phoenix from the ashes: The 5 million year old virus
• Human endogenous retroviruses: from ancestral pathogens to bona fide genes
• Simian foamy virus is widespread in chimpanzees

The asexual erythrocytic phase of the life cycle of Plasmodium falciparum produces the clinical symptoms, disease and pathology associated with malaria. During this phase, merozoites released from schizont-infected erythrocytes invade uninfected erythrocytes. Invasion depends on distinct molecular interactions between ligands on the merozoite, the invasive form of the parasite, and host receptors on the erythrocyte membrane. To avoid infection, humans have evolved to eliminate or modify erythrocyte surface proteins that serve as receptors for parasite invasion. Perhaps one of the best examples of this evolutionary process is the loss of the Duffy blood group in Africa. Plasmodium vivax depends on two ligands for erythrocyte invasion: the Duffy-binding protein (DBP) that binds the Duffy blood group antigen and the reticulocyte homology protein that binds to an unknown receptor on reticulocytes.

Unlike P. vivax, P. falciparum has highly redundant, alternate invasion pathways that use several different receptor families. P. vivax has only one gene, DBP, in the Duffybinding-like erythrocyte-binding protein (DBL-EBP) family, whereas P. falciparum has four DBL-EBP genes: erythrocytebinding antigen 175 (EBA-175), erythrocyte-binding antigen 140 (BAEBL/EBA-140), erythrocyte-binding antigen 181 (JESEBL/ EBA-181), and erythrocyte-binding ligand-1 (EBL-1). Consequently, no erythrocyte has been identified that is refractory to P. falciparum invasion. A recent paper provides evidence that the fourth DBL-EBP family member, EBL-1, binds to glycophorin B.

Theoretical studies indicate that a null allele of glycophorin B would need to afford only a modest level of protection against malaria in heterozygous to increase in frequency from a single mutant to an allele frequency of 0.59. Assuming a constant population of size 1,000–10,000 individuals, one need invoke a selective advantage of only 1% in homozygous-null genotypes to have a single copy of the null mutant allele increase to a frequency of 59% across an interval of 100,000 years (5,000 generations). A shorter time entails stronger selection, but even for 10,000 years (500 generations), a selective advantage of only 10% in homozygous-null genotypes is required. Both cases require partial dominance corresponding to 10–20% as much protection in heterozygous genotypes as in the homozygous-null.

Glycophorin B is the erythrocyte receptor of Plasmodium falciparum erythrocyte-binding ligand, EBL-1. PNAS USA March 11, 2009
In the war against Plasmodium, humans have evolved to eliminate or modify proteins on the erythrocyte surface that serve as receptors for parasite invasion, such as the Duffy blood group, a receptor for Plasmodium vivax, and the Gerbich-negative modification of glycophorin C for Plasmodium falciparum. In turn, the parasite counters with expansion and diversification of ligand families. The high degree of polymorphism in glycophorin B found in malaria-endemic regions suggests that it also may be a receptor for Plasmodium, but, to date, none has been identified. We provide evidence from erythrocyte-binding that glycophorin B is a receptor for the P. falciparum protein EBL-1, a member of the Duffy-binding-like erythrocyte-binding protein (DBL-EBP) receptor family. The erythrocyte-binding domain, region 2 of EBL-1, expressed on CHO-K1 cells, bound glycophorin B+ but not glycophorin B-null erythrocytes. In addition, glycophorin B+ but not glycophorin B-null erythrocytes adsorbed native EBL-1 from the P. falciparum culture supernatants. Interestingly, the Efe pygmies of the Ituri forest in the Democratic Republic of the Congo have the highest gene frequency of glycophorin B-null in the world, raising the possibility that the DBL-EBP family may have expanded in response to the high frequency of glycophorin B-null in the population.

Related:

• Malaria: now you see me, now you don’t
• New ways to beat malaria
• Researchers characterize potential protein targets for malaria vaccine