TY - JOUR

T1 - CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses

AU - Russell, Ronnie M

AU - Bibollet-Ruche, Frederic

AU - Liu, Weimin

AU - Sherrill-Mix, Scott

AU - Li, Yingying

AU - Connell, Jesse

AU - Loy, Dorothy E

AU - Trimboli, Stephanie

AU - Smith, Andrew G

AU - Avitto, Alexa N

AU - Gondim, Marcos V P

AU - Plenderleith, Lindsey J

AU - Wetzel, Katherine S

AU - Collman, Ronald G

AU - Ayouba, Ahidjo

AU - Esteban, Amandine

AU - Peeters, Martine

AU - Kohler, William J

AU - Miller, Richard A

AU - François-Souquiere, Sandrine

AU - Switzer, William M

AU - Hirsch, Vanessa M

AU - Marx, Preston A

AU - Piel, Alex K

AU - Stewart, Fiona A

AU - Georgiev, Alexander V

AU - Sommer, Volker

AU - Bertolani, Paco

AU - Hart, John A

AU - Hart, Terese B

AU - Shaw, George M

AU - Sharp, Paul M

AU - Hahn, Beatrice H

PY - 2021/3/26

Y1 - 2021/3/26

N2 - 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 -linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons ( 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. [Abstract copyright: Copyright © 2021 the Author(s). Published by PNAS.]

AB - 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 -linked glycosylation sites, were found in primate species from different genera, providing striking examples of parallel evolution. Moreover, seven different guenons ( 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. [Abstract copyright: Copyright © 2021 the Author(s). Published by PNAS.]

KW - CD4

KW - balancing selection

KW - parallel evolution

KW - primate lentiviruses

KW - trans-specific polymorphism

U2 - 10.1073/pnas.2025914118

DO - 10.1073/pnas.2025914118

M3 - Article

C2 - 33771926

VL - 118

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 13

ER -