Riboflavin transporter: evidence of a role as entry receptor for chimpanzee endogenous retrovirus

Endogenous retroviruses (ERVs) are remnants of ancestral viral infections in germ cells that constitute a substantial proportion of the mammalian genome and are assumed to provide molecular fossil records of ancient infections. Analysis of these sequences may reveal the mechanisms of virus-host co-evolution, viral endogenization, and extinction. Chimpanzee endogenous retrovirus 1 (CERV1), a gamma retrovirus, is estimated to have circulated within primates for ~10 million years, although it is now apparently extinct. In this study, we aimed to gain an understanding of how the extinct CERV1 was transmitted and endogenized. On the basis of the identification of CERV1 fossils in the primate genome and using the expression-cloning method with the human cDNA library, we found that riboflavin transporter human SLC52A2 served as a receptor for CERV1 entry. The ectopic expression of human and chimpanzee SLC52A2 and its related SLC52A1 in heterogenic cells confers susceptibility to infection by CERV1 and porcine endogenous retrovirus (PERV). Virus interference experiments have shown that CERV1 inhibits infection by PERV and vice versa. This finding indicates that CERV1 and PERV belong to the same virus interference group. CERV1 shows infection in a wide range of human and primate cells. Notably, CERV1 infection is observed in human cell lines that express human SLC52A2 abundantly but hardly express human SLC52A1. Although CERV1 has been established to be present at high copy numbers in the great apes (Pan troglodytes, Pan paniscus, and Gorilla gorilla) and 15 Old World monkey species of the Cercopithecinae and Colobinae subfamilies, it is absent in humans and orangutans. CERV1 gene expression is observed in primates, including chimpanzees, suggesting that CERV1 has co-evolved with its hosts. Our results suggest that ERVs may have conferred resistance to viral infections in a convergent evolutionary manner. These findings are significant not only for advancing the field of paleovirology but also in terms of gaining an understanding of the potential risks of viral infection with respect to xenotransplantation, such as that from pigs to humans.