Evolution of primate θ-defensins: a serpentine path to a sweet tooth

Retrocyclins (ancestral human θ-defensins) are cyclic antimicrobial octadecapeptides that interfere with viral uptake and protect human cells from infection by T- and M-tropic strains of HIV-1 in vitro. As are other θ-defensins, retrocyclins are lectins that bind gp120, CD4, and galactosylceramide—all of which are implicated in HIV-1 uptake. Although θ-defensin mRNA transcripts are present in human bone marrow, spleen, thymus, testis, and skeletal muscle, a premature stop codon aborts their translation. We found six θ-defensin (DEFT) genes in the human genome; five on chromosome 8p23 and one on chromosome 1. All six of these pseudogenes, as well as their homologues in chimpanzees and gorillas, contained the same premature stop codon mutation. Whereas we found intact DEFT genes in DNA from several Old World Monkeys, Hylobates syndactylus (a lesser ape) and orangutans, no homologues were present in DNA from six New World Monkeys and five prosimians. We conclude that DEFT genes and θ-defensins arose in Old World Monkeys by mutation of a pre-existing α-defensin gene. Although intact DEFT genes survive in some nonhuman primates, our hominid ancestors lost their ability to produce θ-defensins after the orangutan and hominid lineages diverged. It is possible (but may be difficult to prove) that this mutation rendered our species more susceptible to infection by HIV-1.