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Abstract

CD4 is known to have evolved rapidly in primates, but the reason for this diversification is unknown. Here, we show that polymorphisms in the simian immunodeficiency virus (SIV) envelope (Env) binding domain of the CD4 receptor modulate the susceptibility of chimpanzee CD4+ T cells to SIV infection by interfering with Env–CD4 interactions required for viral entry. Both amino acid substitutions and N-linked glycosylation sites in the D1 domain blocked Env-mediated entry of a number of SIVs, including viruses that infect primates on which chimpanzees prey. These data identify steric hindrance between cell entry receptor-encoded and virus surface protein-encoded glycans as a mechanism of antiviral protection and suggest that selection pressures by primate lentiviruses, both extant and extinct, have shaped the evolution of chimpanzee CD4.Human and simian immunodeficiency viruses (HIV/SIVs) use CD4 as the primary receptor to enter target cells. Here, we show that the chimpanzee CD4 is highly polymorphic, with nine coding variants present in wild populations, and that this diversity interferes with SIV envelope (Env)–CD4 interactions. Testing the replication fitness of SIVcpz strains in CD4+ T cells from captive chimpanzees, we found that certain viruses were unable to infect cells from certain hosts. These differences were recapitulated in CD4 transfection assays, which revealed a strong association between CD4 genotypes and SIVcpz infection phenotypes. The most striking differences were observed for three substitutions (Q25R, Q40R, and P68T), with P68T generating a second N-linked glycosylation site (N66) in addition to an invariant N32 encoded by all chimpanzee CD4 alleles. In silico modeling and site-directed mutagenesis identified charged residues at the CD4–Env interface and clashes between CD4- and Env-encoded glycans as mechanisms of inhibition. CD4 polymorphisms also reduced Env-mediated cell entry of monkey SIVs, which was dependent on at least one D1 domain glycan. CD4 allele frequencies varied among wild chimpanzees, with high diversity in all but the western subspecies, which appeared to have undergone a selective sweep. One allele was associated with lower SIVcpz prevalence rates in the wild. These results indicate that substitutions in the D1 domain of the chimpanzee CD4 can prevent SIV cell entry. Although some SIVcpz strains have adapted to utilize these variants, CD4 diversity is maintained, protecting chimpanzees against infection with SIVcpz and other SIVs to which they are exposed.