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

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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.
Keywords
PAK2, CXCR4, CD3, Thymus, SIV, Nef, HIV, SIMIAN-IMMUNODEFICIENCY-VIRUS, NONPROGRESSIVE HIV-1 INFECTION, RHESUS MACAQUES, TYPE-1 NEF, P21-ACTIVATED KINASE-2, IMMUNOLOGICAL SYNAPSE, TRANSGENIC MICE, REPLICATION, ACTIVATION, EXPRESSION

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Chicago
Van Nuffel, Anouk, Kevin 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.” Retrovirology 10.
APA
Van Nuffel, Anouk, Ariën, K., Stove, V., Schindler, M., O’Neill, E., Schmökel, J., Van de Walle, I., et al. (2013). Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms. RETROVIROLOGY, 10.
Vancouver
1.
Van Nuffel A, Ariën K, Stove V, Schindler M, O’Neill E, Schmökel J, et al. Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms. RETROVIROLOGY. 2013;10.
MLA
Van Nuffel, Anouk, Kevin Ariën, Veronique Stove, et al. “Primate Lentiviral Nef Proteins Deregulate T-cell Development by Multiple Mechanisms.” RETROVIROLOGY 10 (2013): n. pag. Print.
@article{4283690,
  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.},
  articleno    = {137},
  author       = {Van Nuffel, Anouk and Ari{\"e}n, Kevin and Stove, Veronique and Schindler, Michael and O'Neill, Eduardo and Schm{\"o}kel, Jan and Van de Walle, Inge and Naessens, Evelien and Vanderstraeten, Hanne and Van Landeghem, Kathleen and Taghon, Tom and Pulkkinen, Kati and Saksela, Kalle and Garcia, J Victor and Fackler, Oliver T and Kirchhoff, Frank and Verhasselt, Bruno},
  issn         = {1742-4690},
  journal      = {RETROVIROLOGY},
  keyword      = {PAK2,CXCR4,CD3,Thymus,SIV,Nef,HIV,SIMIAN-IMMUNODEFICIENCY-VIRUS,NONPROGRESSIVE HIV-1 INFECTION,RHESUS MACAQUES,TYPE-1 NEF,P21-ACTIVATED KINASE-2,IMMUNOLOGICAL SYNAPSE,TRANSGENIC MICE,REPLICATION,ACTIVATION,EXPRESSION},
  language     = {eng},
  pages        = {13},
  title        = {Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms},
  url          = {http://dx.doi.org/10.1186/1742-4690-10-137},
  volume       = {10},
  year         = {2013},
}

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