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Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms

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dc.contributor.author Van Nuffel, A. en_US
dc.contributor.author Ariën, K. K. en_US
dc.contributor.author Stove, V. en_US
dc.contributor.author Schindler, M. en_US
dc.contributor.author O'Neill, E. en_US
dc.contributor.author Schmökel, J. en_US
dc.contributor.author Van de Walle, I. en_US
dc.contributor.author Naessens, E. en_US
dc.contributor.author Vanderstraeten, H. en_US
dc.contributor.author Van Landeghem, K. en_US
dc.contributor.author Taghon, T. en_US
dc.contributor.author Pulkkinen, K. en_US
dc.contributor.author Saksela, K. en_US
dc.contributor.author Garcia, J. V. en_US
dc.contributor.author Fackler, O. T. en_US
dc.contributor.author Kirchhoff, F. en_US
dc.contributor.author Verhasselt, B. en_US
dc.date.accessioned 2014-09-25T13:39:36Z
dc.date.available 2014-09-25T13:39:36Z
dc.date.issued 2013 en_US
dc.identifier.issn 1742-4690 en_US
dc.identifier.doi http://dx.doi.org/10.1186/1742-4690-10-137 en_US
dc.identifier.other ITG-B2A; DBM; U-VIROL; JIF; DOI; FTA; URL; E-only; Abstract; UPD56 en_US
dc.identifier.uri http://hdl.handle.net/10390/7753
dc.description.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. en_US
dc.language English en_US
dc.subject Viral diseases en_US
dc.subject HIV-1 en_US
dc.subject SIV en_US
dc.subject AIDS en_US
dc.subject Immunodeficiency en_US
dc.subject T-cells en_US
dc.subject Development en_US
dc.subject Nef en_US
dc.subject Proteins en_US
dc.subject p21 en_US
dc.subject Lentivirus en_US
dc.title Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms en_US
dc.type Article-E en_US
dc.citation.issue 137 en_US
dc.citation.jtitle Retrovirology en_US
dc.citation.volume 10 en_US
dc.citation.pages 1-13 en_US
dc.identifier.pmid http://www.ncbi.nlm.nih.gov/pubmed/24237970 en_US
dc.identifier.url http://www.retrovirology.com/content/10/1/137 en_US
dc.citation.jabbreviation Retrovirology en_US


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