Adaptation of CD4 in gorillas and chimpanzees conveyed resistance to simian immunodeficiency viruses
Simian immunodeficiency viruses (SIVs) comprise a large group of primate lentiviruses that endemically infect African monkeys. HIV-1 spilled over to humans from this viral reservoir, but the spillover did not occur directly from monkeys to humans. Instead, a key event was the introduction of SIVs in...
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eLife Sciences Publications Ltd
2025-05-01
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| Online Access: | https://elifesciences.org/articles/93316 |
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| author | Cody J Warren Arturo Barbachano-Guerrero Vanessa L Bauer Alex Stabell Obaiah Dirasantha Qing Yang Sara L Sawyer |
| author_facet | Cody J Warren Arturo Barbachano-Guerrero Vanessa L Bauer Alex Stabell Obaiah Dirasantha Qing Yang Sara L Sawyer |
| author_sort | Cody J Warren |
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| description | Simian immunodeficiency viruses (SIVs) comprise a large group of primate lentiviruses that endemically infect African monkeys. HIV-1 spilled over to humans from this viral reservoir, but the spillover did not occur directly from monkeys to humans. Instead, a key event was the introduction of SIVs into great apes, which then set the stage for infection of humans. Here, we investigate the role of the lentiviral entry receptor, CD4, in this key and fateful event in the history of SIV/HIV emergence. First, we reconstructed and tested ancient forms of CD4 at two important nodes in ape speciation, both prior to the infection of chimpanzees and gorillas with these viruses. These ancestral CD4s fully supported entry of diverse SIV isolates related to the viruses that made this initial jump to apes. In stark contrast, modern chimpanzee and gorilla CD4 orthologs are more resistant to these viruses. To investigate how this resistance in CD4 was gained, we acquired CD4 gene sequences from 32 gorilla individuals of two species and identified alleles that encode 8 unique CD4 protein variants. Functional testing of these identified variant-specific differences in susceptibility to virus entry. By engineering single-point mutations from resistant gorilla CD4 variants into the permissive human CD4 receptor, we demonstrate that acquired substitutions in gorilla CD4 did convey resistance to virus entry. We provide a population genetic analysis to support the theory that selection is acting in favor of more and more resistant CD4 alleles in ape species harboring SIV endemically (gorillas and chimpanzees), but not in other ape species that lack SIV infections (bonobos and orangutans). Taken together, our results show that SIV has placed intense selective pressure on ape CD4, acting to propagate SIV-resistant alleles in chimpanzee and gorilla populations. |
| format | Article |
| id | doaj-art-4aa9d76e607f47de81591d4d0831e62b |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | eLife Sciences Publications Ltd |
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| spelling | doaj-art-4aa9d76e607f47de81591d4d0831e62b2025-08-20T02:31:37ZengeLife Sciences Publications LtdeLife2050-084X2025-05-011310.7554/eLife.93316Adaptation of CD4 in gorillas and chimpanzees conveyed resistance to simian immunodeficiency virusesCody J Warren0https://orcid.org/0000-0003-4101-2705Arturo Barbachano-Guerrero1https://orcid.org/0000-0001-7483-839XVanessa L Bauer2https://orcid.org/0000-0003-0225-3215Alex Stabell3Obaiah Dirasantha4Qing Yang5Sara L Sawyer6https://orcid.org/0000-0002-6965-1085Department of Molecular, Cellular, and Developmental Biology, BioFrontiers Institute, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular, and Developmental Biology, BioFrontiers Institute, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular, and Developmental Biology, BioFrontiers Institute, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular, and Developmental Biology, BioFrontiers Institute, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular, and Developmental Biology, BioFrontiers Institute, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular, and Developmental Biology, BioFrontiers Institute, University of Colorado, Boulder, United StatesDepartment of Molecular, Cellular, and Developmental Biology, BioFrontiers Institute, University of Colorado, Boulder, United StatesSimian immunodeficiency viruses (SIVs) comprise a large group of primate lentiviruses that endemically infect African monkeys. HIV-1 spilled over to humans from this viral reservoir, but the spillover did not occur directly from monkeys to humans. Instead, a key event was the introduction of SIVs into great apes, which then set the stage for infection of humans. Here, we investigate the role of the lentiviral entry receptor, CD4, in this key and fateful event in the history of SIV/HIV emergence. First, we reconstructed and tested ancient forms of CD4 at two important nodes in ape speciation, both prior to the infection of chimpanzees and gorillas with these viruses. These ancestral CD4s fully supported entry of diverse SIV isolates related to the viruses that made this initial jump to apes. In stark contrast, modern chimpanzee and gorilla CD4 orthologs are more resistant to these viruses. To investigate how this resistance in CD4 was gained, we acquired CD4 gene sequences from 32 gorilla individuals of two species and identified alleles that encode 8 unique CD4 protein variants. Functional testing of these identified variant-specific differences in susceptibility to virus entry. By engineering single-point mutations from resistant gorilla CD4 variants into the permissive human CD4 receptor, we demonstrate that acquired substitutions in gorilla CD4 did convey resistance to virus entry. We provide a population genetic analysis to support the theory that selection is acting in favor of more and more resistant CD4 alleles in ape species harboring SIV endemically (gorillas and chimpanzees), but not in other ape species that lack SIV infections (bonobos and orangutans). Taken together, our results show that SIV has placed intense selective pressure on ape CD4, acting to propagate SIV-resistant alleles in chimpanzee and gorilla populations.https://elifesciences.org/articles/93316receptorsarms raceadaptation |
| spellingShingle | Cody J Warren Arturo Barbachano-Guerrero Vanessa L Bauer Alex Stabell Obaiah Dirasantha Qing Yang Sara L Sawyer Adaptation of CD4 in gorillas and chimpanzees conveyed resistance to simian immunodeficiency viruses eLife receptors arms race adaptation |
| title | Adaptation of CD4 in gorillas and chimpanzees conveyed resistance to simian immunodeficiency viruses |
| title_full | Adaptation of CD4 in gorillas and chimpanzees conveyed resistance to simian immunodeficiency viruses |
| title_fullStr | Adaptation of CD4 in gorillas and chimpanzees conveyed resistance to simian immunodeficiency viruses |
| title_full_unstemmed | Adaptation of CD4 in gorillas and chimpanzees conveyed resistance to simian immunodeficiency viruses |
| title_short | Adaptation of CD4 in gorillas and chimpanzees conveyed resistance to simian immunodeficiency viruses |
| title_sort | adaptation of cd4 in gorillas and chimpanzees conveyed resistance to simian immunodeficiency viruses |
| topic | receptors arms race adaptation |
| url | https://elifesciences.org/articles/93316 |
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