Russell, RM, Bibollet-Ruche, F, Liu, W, Sherrill-Mix, S, Li, Y, Connell, J, Loy, DE, Trimboli, S, Smith, AG, Avitto, AN, Gondim, MVP, Plenderleith, LJ, Wetzel, KS, Collman, RG, Ayouba, A, Esteban, A, Peeters, M, Kohler, WJ, Miller, RA, François-Souquiere, S et al, Switzer, WM, Hirsch, VM, Marx, PA, Piel, AK, Stewart, FA, Georgiev, AV, Sommer, V, Bertolani, P, Hart, JA, Hart, TB, Shaw, GM, Sharp, PM and Hahn, BH (2021) CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses. Proceedings of the National Academy of Sciences of the United States of America, 118 (13). ISSN 0027-8424

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Abstract

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.

Item Type:	Article
Uncontrolled Keywords:	CD4; balancing selection; parallel evolution; primate lentiviruses; trans-specific polymorphism
Subjects:	Q Science > QH Natural history > QH301 Biology Q Science > QL Zoology Q Science > QR Microbiology > QR355 Virology
Divisions:	Biological & Environmental Sciences (from Sep 19)
Publisher:	National Academy of Sciences
Related URLs:	Author
Date Deposited:	06 Apr 2021 09:57
Last Modified:	04 Sep 2021 05:38
DOI or ID number:	10.1073/pnas.2025914118
URI:	https://researchonline.ljmu.ac.uk/id/eprint/14751

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