Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms
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Van Nuffel, Anouk, et al. Primate Lentiviral Nef Proteins Deregulate T-cell Development by Multiple Mechanisms. BioMed Central Ltd, 2013. https://doi.org/10.17615/w8pj-q745APA
Van Nuffel, A., Ariën, K., Stove, V., Schindler, M., O’neill, E., Schmökel, J., Van De Walle, I., Naessens, E., Vanderstraeten, H., Van Landeghem, K., Taghon, T., Pulkkinen, K., Saksela, K., Garcia, J., Fackler, O., Kirchhoff, F., & Verhasselt, B. (2013). Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms. BioMed Central Ltd. https://doi.org/10.17615/w8pj-q745Chicago
Van Nuffel, Anouk, Kevin K Ariën, Veronique Stove, Michael Schindler, Eduardo O’neill, Jan Schmökel, Inge Van De Walle et al. 2013. Primate Lentiviral Nef Proteins Deregulate T-Cell Development by Multiple Mechanisms. BioMed Central Ltd. https://doi.org/10.17615/w8pj-q745- Creator
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Van Nuffel, Anouk
- Other Affiliation: Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent, Belgium
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Ariën, Kevin K
- Other Affiliation: Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent, Belgium
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Stove, Veronique
- Other Affiliation: Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent, Belgium
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Schindler, Michael
- Other Affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
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O’Neill, Eduardo
- Other Affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas
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Schmökel, Jan
- Other Affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
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Van de Walle, Inge
- Other Affiliation: Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent, Belgium
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Naessens, Evelien
- Other Affiliation: Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent, Belgium
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Vanderstraeten, Hanne
- Other Affiliation: Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent, Belgium
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Van Landeghem, Kathleen
- Other Affiliation: Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent, Belgium
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Taghon, Tom
- Other Affiliation: Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent, Belgium
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Pulkkinen, Kati
- Other Affiliation: Department of Virology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
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Saksela, Kalle
- Other Affiliation: Department of Virology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
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Garcia, J. Victor
- Affiliation: School of Medicine, UNC Center for AIDS Research
- Other Affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas
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Fackler, Oliver T
- Other Affiliation: Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
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Kirchhoff, Frank
- Other Affiliation: Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
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Verhasselt, Bruno
- Other Affiliation: Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent, Belgium
- Abstract
- Background A nef gene is present in all primate lentiviral genomes and is important for high viral loads and progression to AIDS in human or experimental macaque hosts of HIV or SIV, respectively. In these hosts, infection of the thymus results in a decreased output of naive T cells that may contribute to the development of immunodeficiency. We have previously shown that HIV-1 subtype B Nef proteins can block human T-cell development. However, the underlying mechanism(s) and the conservation of this Nef function between different groups of HIV and SIV remained to be determined. Results We investigated whether reduction of thymic output is a conserved function of highly divergent lentiviral Nef proteins including those from both types of human immunodeficiency viruses (HIV-1 and HIV-2), their direct simian counterparts (SIVcpz, SIVgor and SIVsmm, respectively), and some additional SIV strains. We found that expression of most of these nef alleles in thymocyte progenitors impaired T-cell development and reduced thymic output. For HIV-1 Nef, binding to active p21 protein (Cdc42/Rac)-activated kinase (PAK2) was a major determinant of this function. In contrast, selective disruption of PAK2 binding did not eliminate the effect on T-cell development of SIVmac239 Nef, as was shown by expressing mutants in a newly discovered PAK2 activating structural motif (PASM) constituted by residues I117, H121, T218 and Y221, as well as previously described mutants. Rather, down-modulation of cell surface CD3 was sufficient for reduced thymic output by SIVmac Nef, while other functions of SIV Nefs contributed. Conclusions Our results indicate that primate lentiviral Nef proteins impair development of thymocyte precursors into T cells in multiple ways. The interaction of HIV-1 Nef with active PAK2 by HIV-1 seem to be most detrimental, and downregulation of CD3 by HIV-2 and most SIV Nef proteins sufficient for reduced thymic output. Since the reduction of thymic output by Nef is a conserved property of divergent lentiviruses, it is likely to be relevant for peripheral T-cell depletion in poorly adapted primate lentiviral infections.
- Date of publication
- November 15, 2013
- DOI
- Identifier
- Resource type
- Article
- Rights statement
- In Copyright
- Rights holder
- Anouk Van Nuffel et al.; licensee BioMed Central Ltd.
- License
- Journal title
- Retrovirology
- Journal volume
- 10
- Journal issue
- 1
- Page start
- 137
- Language
- English
- Is the article or chapter peer-reviewed?
- Yes
- ISSN
- 1742-4690
- Bibliographic citation
- Retrovirology. 2013 Nov 15;10(1):137
- Publisher
- BioMed Central Ltd
- Access right
- Open Access
- Date uploaded
- August 26, 2015
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