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Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):3229-3238. doi: 10.1073/pnas.1821197116. Epub 2019 Feb 4.

CD4 receptor diversity in chimpanzees protects against SIV infection.

Author information

1
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
2
Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104.
3
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
4
Institute of Evolutionary Biology, University of Edinburgh, EH9 3FL Edinburgh, United Kingdom.
5
Centre for Immunity, Infection and Evolution, University of Edinburgh, EH9 3FL Edinburgh, United Kingdom.
6
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294.
7
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
8
Département de Microbiologie, Infectiologie et Immunologie, Centre de Recherche du Centre Hospitalier de L'Université de Montréal, Montréal, QC H2X0A9, Canada.
9
Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC H2X0A9, Canada.
10
Recherche Translationnelle Appliquée au VIH et aux Maladies Infectieuses, Institut de Recherche pour le Développement, University of Montpellier, INSERM, 34090 Montpellier, France.
11
Research Group Epidemiology of Highly Pathogenic Microorganisms, Robert Koch Institute, 13353 Berlin, Germany.
12
Department of Primatology, Max Planck Institute for Evolutionary Anthropology, 04103 Leipzig, Germany.
13
Chimbo Foundation, 1011 PW Amsterdam, The Netherlands.
14
Projet Primates France, Centre de Conservation pour Chimpanzés, BP 36 Faranah, Republic of Guinea.
15
Department of Anthropology, University of Zurich, CH-8006 Zurich, Switzerland.
16
Sanaga-Yong Chimpanzee Rescue Center, In Defense of Animals-Africa, Portland, OR 97204.
17
Department of Biology, Drexel University, Philadelphia, PA 19104.
18
Department of Anthropology, University of New Mexico, Albuquerque, NM 87131.
19
Department of Anthropology, Washington University in St. Louis, St Louis, MO 63130.
20
Congo Program, Wildlife Conservation Society, BP 14537 Brazzaville, Republic of the Congo.
21
Lester E. Fisher Center for the Study and Conservation of Apes, Lincoln Park Zoo, Chicago, IL 60614.
22
Tchimpounga Chimpanzee Rehabilitation Center, The Jane Goodall Institute-Congo, BP 1206 Pointe Noire, Republic of Congo.
23
Africa Programs, The Jane Goodall Institute, Vienna, VA 22182.
24
School of Natural Sciences and Psychology, Liverpool John Moores University, L3 3AF Liverpool, United Kingdom.
25
Department of Ecology and Management of Plant and Animal Resources, Faculty of Sciences, University of Kisangani, BP 2012 Kisangani, Democratic Republic of the Congo.
26
Gombe Stream Research Centre, The Jane Goodall Institute, Kigoma, Tanzania.
27
Department of Psychology, Franklin and Marshall College, Lancaster, PA 17604.
28
Department of Evolutionary Anthropology, Duke University, Durham, NC 27708.
29
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104; bhahn@pennmedicine.upenn.edu.

Abstract

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.

KEYWORDS:

CD4; SIV; chimpanzee; envelope glycoprotein; glycan restriction

PMID:
30718403
PMCID:
PMC6386711
DOI:
10.1073/pnas.1821197116
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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