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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Autores principales: 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
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Publicado: Public Library of Science (PLoS) 2012
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Acceso en línea:https://doaj.org/article/f4dc536a7092459b97d0a541b72626f2
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spelling 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)
institution DOAJ
collection DOAJ
language EN
topic Immunologic diseases. Allergy
RC581-607
Biology (General)
QH301-705.5
spellingShingle 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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