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Differential regulation of NF-?B-mediated proviral and antiviral host gene expression by primate lentiviral Nef and Vpu proteins.

ABSTRACT: NF-?B is essential for effective transcription of primate lentiviral genomes and also activates antiviral host genes. Here, we show that the early protein Nef of most primate lentiviruses enhances NF-?B activation. In contrast, the late protein Vpu of HIV-1 and its simian precursors inhibits activation of NF-?B, even in the presence of Nef. Although this effect of Vpu did not correlate with its ability to interact with ?-TrCP, it involved the stabilization of I?B and reduced nuclear translocation of p65. Interestingly, however, Vpu did not affect casein kinase II-mediated phosphorylation of p65. Lack of Vpu was associated with increased NF-?B activation and induction of interferon and interferon-stimulated genes (ISGs) in HIV-1-infected T cells. Thus, HIV-1 and its simian precursors employ Nef to boost NF-?B activation early during the viral life cycle to initiate proviral transcription, while Vpu is used to downmodulate NF-?B-dependent expression of ISGs at later stages.

SUBMITTER: Sauter D

PROVIDER: S-EPMC4682570 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Publications

Differential regulation of NF-κB-mediated proviral and antiviral host gene expression by primate lentiviral Nef and Vpu proteins.

Sauter Daniel D Hotter Dominik D Van Driessche Benoît B Stürzel Christina M CM Kluge Silvia F SF Wildum Steffen S Yu Hangxing H Baumann Bernd B Wirth Thomas T Plantier Jean-Christophe JC Leoz Marie M Hahn Beatrice H BH Van Lint Carine C Kirchhoff Frank F

Cell reports 20150122 4

NF-κB is essential for effective transcription of primate lentiviral genomes and also activates antiviral host genes. Here, we show that the early protein Nef of most primate lentiviruses enhances NF-κB activation. In contrast, the late protein Vpu of HIV-1 and its simian precursors inhibits activation of NF-κB, even in the presence of Nef. Although this effect of Vpu did not correlate with its ability to interact with β-TrCP, it involved the stabilization of IκB and reduced nuclear translocatio ...[more]

PMID: 25620704

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Project description:BackgroundA 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.ResultsWe 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.ConclusionsOur 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.

Dataset Information

Differential regulation of NF-?B-mediated proviral and antiviral host gene expression by primate lentiviral Nef and Vpu proteins.

Publications

Differential regulation of NF-κB-mediated proviral and antiviral host gene expression by primate lentiviral Nef and Vpu proteins.

Similar Datasets

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