CD4 receptor diversity in chimpanzees protects against SIV infection

Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):3229-3238. doi: 10.1073/pnas.1821197116. Epub 2019 Feb 4.


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.

Keywords: CD4; SIV; chimpanzee; envelope glycoprotein; glycan restriction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4 Antigens / genetics*
  • CD4 Antigens / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • Evolution, Molecular
  • Genetic Variation / immunology
  • HIV / genetics
  • HIV / pathogenicity
  • Humans
  • Pan troglodytes / genetics
  • Pan troglodytes / immunology
  • Polysaccharides / genetics
  • Polysaccharides / immunology
  • Simian Acquired Immunodeficiency Syndrome / genetics*
  • Simian Acquired Immunodeficiency Syndrome / immunology
  • Simian Acquired Immunodeficiency Syndrome / virology
  • Simian Immunodeficiency Virus / genetics*
  • Simian Immunodeficiency Virus / pathogenicity
  • Viral Envelope Proteins / genetics*
  • Viral Envelope Proteins / immunology


  • CD4 Antigens
  • Polysaccharides
  • Viral Envelope Proteins

Associated data

  • GENBANK/MK178722
  • GENBANK/MK178852
  • GENBANK/MK208828
  • GENBANK/MK208836
  • GENBANK/MK208839
  • GENBANK/MK208845