CD4 Receptor Diversity among African Primates Protects against SIV Infection

The global HIV-1 epidemic is the result of a cross-species transmission of a simian immunodeficiency virus that infects chimpanzees (SIVcpz). There have been no fewer than 12 SIV strains that have crossed into humans: two from chimpanzees, two from western lowland gorillas, and at least eight from sooty mangabeys. The 40+ African primates endemically infected by related lentiviruses thus represent a vast reservoir of SIVs with the potential to generate human pathogens, necessitating the study of these viruses and their evolutionary history. Because of its relatedness to HIV-1, we looked for factors that limit the spread and replication of SIVcpz in chimpanzees. We identified substantial diversity among chimpanzees in CD4, the primary receptor used by all primate lentiviruses, with nine unique variants present in wild populations. These variants were shown to be protective against some, but not all, strains of SIVcpz, both in in vitro entry assays and in primary chimpanzee cells. Consistent with this, wild chimpanzees with certain genotypes were less likely to be infected by SIVcpz in the wild. Surprisingly, these CD4 variants also protected against SIVs that infect monkey species on which chimpanzees prey, suggesting CD4 diversity evolved in part because of cross-species transmission threats. To address whether protective CD4 diversity likewise evolved in other primates, we performed a comprehensive analysis on 26 African primate species, generating CD4 sequences from multiple individuals of each species and functionally testing a subset. In total, 22 of 26 species exhibited within-species diversity in the SIV Envelope (Env) binding domain of CD4, and many of these variants altered entry by a panel of SIV strains. As a striking example of convergent evolution, we identified several instances of identical polymorphisms in divergent primate species. These included changes to CD4 residues that make direct contact with Env and toggling of six unique glycosylation sites, both shown to be protective mechanisms when functionally assayed. Altogether, these data establish CD4 diversity, both within and between species, as a barrier that limits the spread of primate lentiviruses