CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses

Ronnie M. Russell, Frederic Bibollet-Ruche, Weimin Liu, Scott Sherrill-Mix, Yingying Li, Jesse Connell, Dorothy E. Loy, Stephanie Trimboli, Andrew G. Smith, Alexa N. Avitto, Marcos V. P. Gondim, Lindsey J. Plenderleith, Katherine S. Wetzel, Ronald G. Collman, Ahidjo Ayouba, Amandine Esteban, Martine Peeters, William J. Kohler, Richard A. Miller, Sandrine François-SouquiereWilliam M. Switzer, Vanessa M. Hirsch, Preston A. Marx, Alex K. Piel, Fiona A. Stewart, Alexander V. Georgiev, Volker Sommer, Paco Bertolani, John A. Hart, Terese B. Hart, George M. Shaw, Paul M. Sharp, Beatrice H. Hahn

Research output: Contribution to journalArticlepeer-review


Infection with human and simian immunodeficiency viruses (HIV/SIV) requires binding of the viral envelope glycoprotein (Env) to the host protein CD4 on the surface of immune cells. Although invariant in humans, the Env binding domain of the chimpanzee CD4 is highly polymorphic, with nine coding variants circulating in wild populations. Here, we show that within-species CD4 diversity is not unique to chimpanzees but found in many African primate species. Characterizing the outermost (D1) domain of the CD4 protein in over 500 monkeys and apes, we found polymorphic residues in 24 of 29 primate species, with as many as 11 different coding variants identified within a single species. D1 domain amino acid replacements affected SIV Env-mediated cell entry in a single-round infection assay, restricting infection in a strain- and allele-specific fashion. Several identical CD4 polymorphisms, including the addition of N-linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons (Cercopithecus spp.) shared multiple distinct D1 domain variants, pointing to long-term trans-specific polymorphism. These data indicate that the HIV/SIV Env binding region of the primate CD4 protein is highly variable, both within and between species, and suggest that this diversity has been maintained by balancing selection for millions of years, at least in part to confer protection against primate lentiviruses. Although long-term SIV-infected species have evolved specific mechanisms to avoid disease progression, primate lentiviruses are intrinsically pathogenic and have left their mark on the host genome.
Original languageEnglish
Article numbere2025914118
JournalProceedings of the National Academy of Sciences (PNAS)
Issue number13
Publication statusPublished - 30 Mar 2021


  • CD4
  • primate lentiviruses
  • parallel evolution
  • trans-specific polymorphism
  • balancing selection


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