Hyper-responsiveness to Stimulation of Human Immunodeficiency Virus-infected CD4+ T Cells Requires Nef and Tat Virus Gene Products and Results from Higher NFAT, NF-κB, and AP-1 Induction

Fortin, Jean-François; Barat, Corinne; Beauséjour, Yannick; Barbeau, Benoı̂t; Tremblay, Michel J.

doi:10.1074/jbc.m407477200

Cited by 87 publications

(98 citation statements)

References 86 publications

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“…Tat is essential for replication of the viral genome, and it has been proposed that Tat is an important factor in HIV-induced pathogenesis of AIDS (2). Exogenous Tat has a variety of effects on cellular processes in uninfected cells, including increased binding of nuclear factor kappa B (NF-B) to DNA, increased production of cytokines, increased expression of cytokine receptors, and modulation of cell survival and proliferation (2,19,31,34,42). Furthermore, studies have demonstrated that Tat increases apoptosis in a variety of cell types, including cell types not directly infected by HIV-1 (4,42).…”

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confidence: 99%

The Human Immunodeficiency Virus Type 1 Tat Protein EnhancesCryptosporidium parvum-Induced Apoptosis in Cholangiocytes via a Fas Ligand-Dependent Mechanism

et al. 2007

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While Cryptosporidium parvum infection of the intestine has been reported in both immunocompetent and immunocompromised individuals, biliary infection is seen primarily in adult AIDS patients and is associated with development of AIDS cholangiopathy. However, the mechanisms of pathogen-induced AIDS cholangiopathy remain unclear. Since we previously demonstrated that the Fas/Fas ligand (FasL) system is involved in paracrine-mediated C. parvum cytopathicity in cholangiocytes, we also tested the potential synergistic effects of human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat)-mediated FasL regulation on C. parvum-induced apoptosis in cholangiocytes by semiquantitative reverse transcription-PCR, immunoblotting, immunofluorescence analysis, and immunogold electron microscopy. H69 cells do not express CXCR4 and CCR5, which are receptors required for direct HIV-1 viral infection. However, recombinant biologically active HIV-1-associated Tat protein increased FasL expression in the cytoplasm of cholangiocytes without a significant increase in apoptosis. We found that C. parvum-induced apoptosis was associated with translocation of intracellular FasL to the cell membrane surface and release of full-length FasL from infected H69 cells. Tat significantly (P < 0.05) increased C. parvum-induced apoptosis in bystander cells in a dose-dependent manner. Moreover, Tat enhanced both C. parvum-induced FasL membrane translocation and release of full-length FasL. In addition, the FasL neutralizing antibody NOK-1 and the caspase-8 inhibitor Z-IETD-fmk both blocked C. parvum-induced apoptosis in cholangiocytes. The data demonstrated that HIV-1 Tat enhances C. parvum-induced cholangiocyte apoptosis via a paracrine-mediated, FasL-dependent mechanism. Our results suggest that concurrent active HIV replication, with associated production of Tat protein, and C. parvum infection synergistically increase cholangiocyte apoptosis and thus jointly contribute to AIDS-related cholangiopathies.

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The Human Immunodeficiency Virus Type 1 Tat Protein EnhancesCryptosporidium parvum-Induced Apoptosis in Cholangiocytes via a Fas Ligand-Dependent Mechanism

et al. 2007

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“…In addition, Nef affects the basal states of T cell activation and the responsiveness of T lymphocytes to TCR signaling (24)(25)(26)(27) with the majority of studies that addressed effects of Nef on distal responses to exogenous TCR stimulation by mitogens or anti-TCR Abs reporting a moderate enhancement by HIV-1 Nef (16,(28)(29)(30)(31)(32)(33)(34). In contrast, HIV-1 Nef severely impairs the formation and organization of IS structures between Nef-expressing T lymphocytes and APCs by reducing the frequency of IS formation, blocking Factin polarization at cell-cell contacts, and inducing mislocalization of the TCR itself as well as its effector kinase Lck (28,(35)(36)(37)(38)(39).…”

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HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

Abraham

Bankhead

Pan

et al. 2012

The Journal of Immunology

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Signal initiation by engagement of the TCR triggers actin rearrangements, receptor clustering, and dynamic organization of signaling complexes to elicit and sustain downstream signaling. Nef, a pathogenicity factor of HIV, disrupts early TCR signaling in target T cells. To define the mechanism underlying this Nef-mediated signal disruption, we employed quantitative single-cell microscopy following surface-mediated TCR stimulation that allows for dynamic visualization of distinct signaling complexes as microclusters (MCs). Despite marked inhibition of actin remodeling and cell spreading, the induction of MCs containing TCR-CD3 or ZAP70 was not affected significantly by Nef. However, Nef potently inhibited the subsequent formation of MCs positive for the signaling adaptor Src homology-2 domain-containing leukocyte protein of 76 kDa (SLP-76) to reduce MC density in Nef-expressing and HIV-1–infected T cells. Further analyses suggested that Nef prevents formation of SLP-76 MCs at the level of the upstream adaptor protein, linker of activated T cells (LAT), that couples ZAP70 to SLP-76. Nef did not disrupt pre-existing MCs positive for LAT. However, the presence of the viral protein prevented de novo recruitment of active LAT into MCs due to retargeting of LAT to an intracellular compartment. These modulations in MC formation and composition depended on Nef’s ability to simultaneously disrupt both actin remodeling and subcellular localization of TCR-proximal machinery. Nef thus employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 and preventing the dynamic formation of SLP-76–signaling MCs.

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“…These effector functions probably reflect the ability of Nef to serve as a protein-interaction adaptor that modulates cellular vesicle transport and signal transduction machineries (5,6). In CD4 ϩ T-lymphocytes, one of the major HIV-1 target cell populations in vivo, Nef lowers the threshold of TCR activation possibly to induce an intermediate activation state that is permissive for HIV-1 replication (7)(8)(9)(10)(11)(12). Several protein assemblies, including the association with the Nef-associated kinase complex, the guanine exchange factors Vav and DOCK2-ELMO1, and the TCR chain, are involved in the modulation of TCR signaling by Nef (13)(14)(15)(16).…”

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The HIV-1 Pathogenicity Factor Nef Interferes with Maturation of Stimulatory T-lymphocyte Contacts by Modulation of N-Wasp Activity

Haller

Rauch

Michel

et al. 2006

Journal of Biological Chemistry

148

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The Nef protein is a key determinant of human immunodeficiency virus (HIV) pathogenicity that, among other activities, sensitizes T-lymphocytes for optimal virus production. The initial events by which Nef modulates the T-cell receptor (TCR) cascade are poorly understood.TCRengagementtriggersactinrearrangementsthatcontrol receptor clustering for signal initiation and dynamic organization of signaling protein complexes to form an immunological synapse. Here we report that Nef potently interferes with cell spreading and formation of actin-rich circumferential rings in T-lymphocytes upon surface-supported TCR stimulation. These effects were conserved among Nef proteins from different lentiviruses and occurred in HIV-1-infected primary human T-lymphocytes. This novel Nef activity critically depended on its Src homology 3 domain binding motif and required efficient association with Pak2 activity. Notably, whereas overall signaling microcluster formation immediately following TCR engagement occurred normally in Nef-expressing cells, the viral protein inhibited the concomitant activation of the actin organizer N-Wasp. During the subsequent maturation phase of the stimulatory contact, Nef interfered with the translocation of N-Wasp to the cell periphery, the overall induction of tyrosine phosphorylation, and the selective recruitment of phosphorylated LAT to stimulatory contacts. Consistent with such a critical role of N-Wasp in this process, Nef also blocked morphological changes induced by the known N-Wasp regulators Rac1 and Cdc42. Together, our results demonstrate that Nef alters both the amount and composition of signaling microclusters. We propose modulation of actin dynamics as an important mechanism for Nef-induced alterations of TCR signaling.The Nef protein of the primate lentiviruses HIV-1/-2 2 and simian immunodeficiency virus is a crucial pathogenicity factor and substantially increases virus replication in vivo (1-4). Whereas the underlying molecular mechanisms remain to be fully elucidated, Nef facilitates immune evasion of infected cells and directly boosts virus spread. These effector functions probably reflect the ability of Nef to serve as a protein-interaction adaptor that modulates cellular vesicle transport and signal transduction machineries (5, 6). In CD4 ϩ T-lymphocytes, one of the major HIV-1 target cell populations in vivo, Nef lowers the threshold of TCR activation possibly to induce an intermediate activation state that is permissive for HIV-1 replication (7-12). Several protein assemblies, including the association with the Nef-associated kinase complex, the guanine exchange factors Vav and DOCK2-ELMO1, and the TCR chain, are involved in the modulation of TCR signaling by Nef (13-16). However, it has not been addressed how Nef affects early events of TCR signal initiation. Physiologically, TCR triggering occurs in the context of a close contact between a T-cell and antigenpresenting cell referred to as the immunological synapse (IS). Within this highly dynamic structure, spatial redistribut...

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Hyper-responsiveness to Stimulation of Human Immunodeficiency Virus-infected CD4+ T Cells Requires Nef and Tat Virus Gene Products and Results from Higher NFAT, NF-κB, and AP-1 Induction

Cited by 87 publications

References 86 publications

The Human Immunodeficiency Virus Type 1 Tat Protein EnhancesCryptosporidium parvum-Induced Apoptosis in Cholangiocytes via a Fas Ligand-Dependent Mechanism

The Human Immunodeficiency Virus Type 1 Tat Protein EnhancesCryptosporidium parvum-Induced Apoptosis in Cholangiocytes via a Fas Ligand-Dependent Mechanism

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

The HIV-1 Pathogenicity Factor Nef Interferes with Maturation of Stimulatory T-lymphocyte Contacts by Modulation of N-Wasp Activity

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