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CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses.

Russell, RM; Bibollet-Ruche, F; Liu, W; Sherrill-Mix, S; Li, Y; Connell, J; Loy, DE; ... Hahn, BH; + view all (2021) CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses. Proceedings of the National Academy of Sciences , 118 (13) , Article e20259141. 10.1073/pnas.2025914118. Green open access

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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.

Type: Article
Title: CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.2025914118
Publisher version: https://doi.org/10.1073/pnas.2025914118
Language: English
Additional information: This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Keywords: CD4, balancing selection, parallel evolution, primate lentiviruses, trans-specific polymorphism
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL SLASH
UCL > Provost and Vice Provost Offices > UCL SLASH > Faculty of S&HS
UCL > Provost and Vice Provost Offices > UCL SLASH > Faculty of S&HS > Dept of Anthropology
URI: https://discovery.ucl.ac.uk/id/eprint/10126170
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