Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein.
HIV-1 groups M and N emerged within the last century following two independent cross-species transmissions of SIVcpz from chimpanzees to humans. In contrast to pandemic group M strains, HIV-1 group N viruses are exceedingly rare, with only about a dozen infections identified, all but one in individu...
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2012
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oai:doaj.org-article:f4dc536a7092459b97d0a541b72626f22021-11-18T06:06:14ZHuman tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein.1553-73661553-737410.1371/journal.ppat.1003093https://doaj.org/article/f4dc536a7092459b97d0a541b72626f22012-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23308067/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374HIV-1 groups M and N emerged within the last century following two independent cross-species transmissions of SIVcpz from chimpanzees to humans. In contrast to pandemic group M strains, HIV-1 group N viruses are exceedingly rare, with only about a dozen infections identified, all but one in individuals from Cameroon. Poor adaptation to the human host may be responsible for this limited spread of HIV-1 group N in the human population. Here, we analyzed the function of Vpu proteins from seven group N strains from Cameroon, the place where this zoonosis originally emerged. We found that these N-Vpus acquired four amino acid substitutions (E15A, V19A and IV25/26LL) in their transmembrane domain (TMD) that allow efficient interaction with human tetherin. However, despite these adaptive changes, most N-Vpus still antagonize human tetherin only poorly and fail to down-modulate CD4, the natural killer (NK) cell ligand NTB-A as well as the lipid-antigen presenting protein CD1d. These functional deficiencies were mapped to amino acid changes in the cytoplasmic domain that disrupt putative adaptor protein binding sites and an otherwise highly conserved ßTrCP-binding DSGxxS motif. As a consequence, N-Vpus exhibited aberrant intracellular localization and/or failed to recruit the ubiquitin-ligase complex to induce tetherin degradation. The only exception was the Vpu of a group N strain recently discovered in France, but originally acquired in Togo, which contained intact cytoplasmic motifs and counteracted tetherin as effectively as the Vpus of pandemic HIV-1 M strains. These results indicate that HIV-1 group N Vpu is under strong host-specific selection pressure and that the acquisition of effective tetherin antagonism may lead to the emergence of viral variants with increased transmission fitness.Daniel SauterDaniel UnterwegerMichael VoglShariq M UsmaniAnke HeigeleSilvia F KlugeElisabeth HermkesMarkus MollEdward BarkerMartine PeetersGerald H LearnFrederic Bibollet-RucheJoëlle V FritzOliver T FacklerBeatrice H HahnFrank KirchhoffPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 12, p e1003093 (2012) |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
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Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Daniel Sauter Daniel Unterweger Michael Vogl Shariq M Usmani Anke Heigele Silvia F Kluge Elisabeth Hermkes Markus Moll Edward Barker Martine Peeters Gerald H Learn Frederic Bibollet-Ruche Joëlle V Fritz Oliver T Fackler Beatrice H Hahn Frank Kirchhoff Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein. |
description |
HIV-1 groups M and N emerged within the last century following two independent cross-species transmissions of SIVcpz from chimpanzees to humans. In contrast to pandemic group M strains, HIV-1 group N viruses are exceedingly rare, with only about a dozen infections identified, all but one in individuals from Cameroon. Poor adaptation to the human host may be responsible for this limited spread of HIV-1 group N in the human population. Here, we analyzed the function of Vpu proteins from seven group N strains from Cameroon, the place where this zoonosis originally emerged. We found that these N-Vpus acquired four amino acid substitutions (E15A, V19A and IV25/26LL) in their transmembrane domain (TMD) that allow efficient interaction with human tetherin. However, despite these adaptive changes, most N-Vpus still antagonize human tetherin only poorly and fail to down-modulate CD4, the natural killer (NK) cell ligand NTB-A as well as the lipid-antigen presenting protein CD1d. These functional deficiencies were mapped to amino acid changes in the cytoplasmic domain that disrupt putative adaptor protein binding sites and an otherwise highly conserved ßTrCP-binding DSGxxS motif. As a consequence, N-Vpus exhibited aberrant intracellular localization and/or failed to recruit the ubiquitin-ligase complex to induce tetherin degradation. The only exception was the Vpu of a group N strain recently discovered in France, but originally acquired in Togo, which contained intact cytoplasmic motifs and counteracted tetherin as effectively as the Vpus of pandemic HIV-1 M strains. These results indicate that HIV-1 group N Vpu is under strong host-specific selection pressure and that the acquisition of effective tetherin antagonism may lead to the emergence of viral variants with increased transmission fitness. |
format |
article |
author |
Daniel Sauter Daniel Unterweger Michael Vogl Shariq M Usmani Anke Heigele Silvia F Kluge Elisabeth Hermkes Markus Moll Edward Barker Martine Peeters Gerald H Learn Frederic Bibollet-Ruche Joëlle V Fritz Oliver T Fackler Beatrice H Hahn Frank Kirchhoff |
author_facet |
Daniel Sauter Daniel Unterweger Michael Vogl Shariq M Usmani Anke Heigele Silvia F Kluge Elisabeth Hermkes Markus Moll Edward Barker Martine Peeters Gerald H Learn Frederic Bibollet-Ruche Joëlle V Fritz Oliver T Fackler Beatrice H Hahn Frank Kirchhoff |
author_sort |
Daniel Sauter |
title |
Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein. |
title_short |
Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein. |
title_full |
Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein. |
title_fullStr |
Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein. |
title_full_unstemmed |
Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein. |
title_sort |
human tetherin exerts strong selection pressure on the hiv-1 group n vpu protein. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2012 |
url |
https://doaj.org/article/f4dc536a7092459b97d0a541b72626f2 |
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