A balancing act between primate lentiviruses and their receptor

Abstract

The receptor for primate lentiviruses, including HIV-1, is the CD4 glycoprotein found on myeloid and T helper cells. CD4 also plays a critical role in mediating adaptive immune responses and in immune cell differentiation by coordinating interactions between T cell receptors and major histocompatibility complex (MHC) proteins (1). This sets up a complex evolutionary challenge as CD4 evolves to escape from pathogenic lentiviruses (2) while maintaining its essential functions in immunity. In PNAS, Russell et al. (3) reveal an added facet of this conflict. They discover that multiple primate species have maintained expression of divergent CD4 alleles, which are functionally distinct in their ability to mediate entry by different lentiviruses, over millions of years. The findings highlight the ancient and ongoing impact of pathogenic viruses in shaping primate genomes. Primate lentiviral envelope proteins interact with the D1 domain of CD4 to enable virus–cell membrane fusion and viral entry (4). A previous analysis revealed significant polymorphism in the D1 domain from CD4 alleles of chimpanzee populations. Some variants were able to protect against infection by simian immunodeficiency virus (SIV) strains in vitro and perhaps also in vivo (5). In the latest study, Russell et al. (3) extend their population surveys to a large panel of primate species and uncover a remarkable degree of variation in the D1 domain in 26 of the 29 surveyed primate species. D1 polymorphism levels varied from nonexistent in species like humans and baboons to remarkably high in some monkey species such as mustached monkeys. Expression of CD4 variants in cells reveals functional differences in their use as entry receptors by various SIV strains. Thus, the most likely hypothesis to explain this high degree of CD4 polymorphism within populations is persistent and ongoing pressure from primate lentiviruses. The signals of balancing selection in CD4 did not strictly … [↵][1]1To whom correspondence may be addressed. Email: hsmalik{at}fhcrc.org or mohainle{at}fredhutch.org. [1]: #xref-corresp-1-1