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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. Copyright © 2019 the Author(s). Published by PNAS.


Frederic Bibollet-Ruche, Ronnie M Russell, Weimin Liu, Guillaume B E Stewart-Jones, Scott Sherrill-Mix, Yingying Li, Gerald H Learn, Andrew G Smith, Marcos V P Gondim, Lindsey J Plenderleith, Julie M Decker, Juliet L Easlick, Katherine S Wetzel, Ronald G Collman, Shilei Ding, Andrés Finzi, Ahidjo Ayouba, Martine Peeters, Fabian H Leendertz, Joost van Schijndel, Annemarie Goedmakers, Els Ton, Christophe Boesch, Hjalmar Kuehl, Mimi Arandjelovic, Paula Dieguez, Mizuki Murai, Christelle Colin, Kathelijne Koops, Sheri Speede, Mary K Gonder, Martin N Muller, Crickette M Sanz, David B Morgan, Rebecca Atencia, Debby Cox, Alex K Piel, Fiona A Stewart, Jean-Bosco N Ndjango, Deus Mjungu, Elizabeth V Lonsdorf, Anne E Pusey, Peter D Kwong, Paul M Sharp, George M Shaw, Beatrice H Hahn. CD4 receptor diversity in chimpanzees protects against SIV infection. Proceedings of the National Academy of Sciences of the United States of America. 2019 Feb 19;116(8):3229-3238

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PMID: 30718403

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