scholarly journals Efficient Non-Epigenetic Activation of HIV Latency through the T-Cell Receptor Signalosome

Viruses ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 868
Author(s):  
Joseph Hokello ◽  
Adhikarimayum Lakhikumar Sharma ◽  
Mudit Tyagi
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell Receptor ◽  
Elongation Factor ◽  
Cell Receptor ◽  
Hiv Latency ◽  
Transcriptional Elongation ◽  
Nuclear Factor ◽  
Epigenetic Mechanisms ◽  
Hiv 1

Human immunodeficiency virus type-1 (HIV-1) can either undergo a lytic pathway to cause productive systemic infections or enter a latent state in which the integrated provirus remains transcriptionally silent for decades. The ability to latently infect T-cells enables HIV-1 to establish persistent infections in resting memory CD4+ T-lymphocytes which become reactivated following the disruption or cessation of intensive drug therapy. The maintenance of viral latency occurs through epigenetic and non-epigenetic mechanisms. Epigenetic mechanisms of HIV latency regulation involve the deacetylation and methylation of histone proteins within nucleosome 1 (nuc-1) at the viral long terminal repeats (LTR) such that the inhibition of histone deacetyltransferase and histone lysine methyltransferase activities, respectively, reactivates HIV from latency. Non-epigenetic mechanisms involve the nuclear restriction of critical cellular transcription factors such as nuclear factor-kappa beta (NF-κB) or nuclear factor of activated T-cells (NFAT) which activate transcription from the viral LTR, limiting the nuclear levels of the viral transcription transactivator protein Tat and its cellular co-factor positive transcription elongation factor b (P-TEFb), which together regulate HIV transcriptional elongation. In this article, we review how T-cell receptor (TCR) activation efficiently induces NF-κB, NFAT, and activator protein 1 (AP-1) transcription factors through multiple signal pathways and how these factors efficiently regulate HIV LTR transcription through the non-epigenetic mechanism. We further discuss how elongation factor P-TEFb, induced through an extracellular signal-regulated kinase (ERK)-dependent mechanism, regulates HIV transcriptional elongation before new Tat is synthesized and the role of AP-1 in the modulation of HIV transcriptional elongation through functional synergy with NF-κB. Furthermore, we discuss how TCR signaling induces critical post-translational modifications of the cyclin-dependent kinase 9 (CDK9) subunit of P-TEFb which enhances interactions between P-TEFb and the viral Tat protein and the resultant enhancement of HIV transcriptional elongation.

scholarly journals Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor

2008 ◽  
Vol 14 (12) ◽  
pp. 1390-1395 ◽  
Author(s):  
Angel Varela-Rohena ◽  
Peter E Molloy ◽  
Steven M Dunn ◽  
Yi Li ◽  
Megan M Suhoski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Immune Escape ◽  
Cell Receptor ◽  
Hiv 1

scholarly journals Crucial Role for Nuclear Factor of Activated T Cells in T Cell Receptor-mediated Regulation of Human Interleukin-17

2004 ◽  
Vol 279 (50) ◽  
pp. 52762-52771 ◽  
Author(s):  
Xikui K. Liu ◽  
Xin Lin ◽  
Sarah L. Gaffen
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Promoter Activity ◽  
Cell Receptor ◽  
Cross Linking ◽  
Supporting Evidence ◽  
Nuclear Factor ◽  
Tcr Signaling ◽  
Activated T Cells

The biological activities of the inflammatory cytokine interleukin (IL)-17 have been widely studied. However, comparatively little is known about how IL-17 expression is controlled. Here, we examined the basis for transcriptional regulation of the human IL-17 gene. IL-17 secretion was induced in peripheral blood mononuclear cells following anti-CD3 cross-linking to activate the T cell receptor (TCR), and costimulatory signaling through CD28 strongly enhanced CD3-induced IL-17 production. To definecis-acting elements important for IL-17 gene regulation, we cloned 1.25 kb of genomic sequence upstream of the transcriptional start site. This putative promoter was active in Jurkat T cells following CD3 and CD28 cross-linking, and its activity was inhibited by cyclosporin A and MAPK inhibitors. The promoter was also active in Hut102 T cells, which we have shown to secrete IL-17 constitutively. Overexpression of nuclear factor of activated T cells (NFAT) or Ras enhanced IL-17 promoter activity, and studies in Jurkat lines deficient in specific TCR signaling pathways provided supporting evidence for a role for NFAT. To delineate the IL-17 minimal promoter, we created a series of 5′ truncations and identified a region between -232 and -159 that was sufficient for inducible promoter activity. Interestingly, two NFAT sites were located within this region, which bound to NFATc1 and NFATc2 in nuclear extracts from Hut102 and Jurkat cells. Moreover, mutations of these sites dramatically reduced both specific DNA binding and reporter gene activity, and chromatin immunoprecipitation assays showed occupancy of NFAT at this regionin vivo. Together, these data show that NFAT is the crucial sensor of TCR signaling in the IL-17 promoter.

scholarly journals Expression and activation of T cell receptor dependent transcription factors in regulatory T cells

2009 ◽  
Vol 7 (S1) ◽  
Author(s):  
H Bendfeldt ◽  
S Frischbutter ◽  
S Kroeger ◽  
A Radbruch ◽  
R Baumgrass
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Receptor ◽  
Cell Receptor

scholarly journals Hierarchy of signaling thresholds downstream of the T cell receptor and the Tec kinase ITK

2021 ◽  
Vol 118 (35) ◽  
pp. e2025825118
Author(s):  
Michael P. Gallagher ◽  
James M. Conley ◽  
Pranitha Vangala ◽  
Manuel Garber ◽  
Andrea Reboldi ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Signal Strength ◽  
Cell Receptor ◽  
Early Gene ◽  
Sequencing Analysis ◽  
Nuclear Factor ◽  
Activated T Cells

The strength of peptide:MHC interactions with the T cell receptor (TCR) is correlated with the time to first cell division, the relative scale of the effector cell response, and the graded expression of activation-associated proteins like IRF4. To regulate T cell activation programming, the TCR and the TCR proximal interleukin-2–inducible T cell kinase (ITK) simultaneously trigger many biochemically separate signaling cascades. T cells lacking ITK exhibit selective impairments in effector T cell responses after activation, but under the strongest signaling conditions, ITK activity is dispensable. To gain insight into whether TCR signal strength and ITK activity tune observed graded gene expression through the unequal activation of distinct signaling pathways, we examined Erk1/2 phosphorylation or nuclear factor of activated T cells (NFAT) and nuclear factor (NF)-κB translocation in naïve OT-I CD8+ cell nuclei. We observed the consistent digital activation of NFAT1 and Erk1/2, but NF-κB displayed dynamic, graded activation in response to variation in TCR signal strength, tunable by treatment with an ITK inhibitor. Inhibitor-treated cells showed the dampened induction of AP-1 factors Fos and Fosb, NF-κB response gene transcripts, and survival factor Il2 transcripts. ATAC sequencing analysis also revealed that genomic regions most sensitive to ITK inhibition were enriched for NF-κB and AP-1 motifs. Specific inhibition of NF-κB during peptide stimulation tuned the expression of early gene products like c-Fos. Together, these data indicate a key role for ITK in orchestrating the optimal activation of separate TCR downstream pathways, specifically aiding NF-κB activation. More broadly, we revealed a mechanism by which variations in TCR signal strength can produce patterns of graded gene expression in activated T cells.

scholarly journals T-Cell Receptor-Mediated Anergy of a Human Immunodeficiency Virus (HIV) gp120-Specific CD4+ Cytotoxic T-Cell Clone, Induced by a Natural HIV Type 1 Variant Peptide

2000 ◽  
Vol 74 (5) ◽  
pp. 2121-2130 ◽  
Author(s):  
Latifa Bouhdoud ◽  
Patricia Villain ◽  
Abderrazzak Merzouki ◽  
Maximilian Arella ◽  
Clément Couture
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cytotoxic T Cell ◽  
Ctl Response ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) infection triggers a cytotoxic T-lymphocyte (CTL) response mediated by CD8+ and perhaps CD4+ CTLs. The mechanisms by which HIV-1 escapes from this CTL response are only beginning to be understood. However, it is already clear that the extreme genetic variability of the virus is a major contributing factor. Because of the well-known ability of altered peptide ligands (APL) to induce a T-cell receptor (TCR)-mediated anergic state in CD4+ helper T cells, we investigated the effects of HIV-1 sequence variations on the proliferation and cytotoxic activation of a human CD4+ CTL clone (Een217) specific for an epitope composed of amino acids 410 to 429 of HIV-1 gp120. We report that a natural variant of this epitope induced a functional anergic state rendering the T cells unable to respond to their antigenic ligand and preventing the proliferation and cytotoxic activation normally induced by the original antigenic peptide. Furthermore, the stimulation of Een217 cells with this APL generated altered TCR-proximal signaling events that have been associated with the induction of T-cell anergy in CD4+ T cells. Importantly, the APL-induced anergic state of the Een217 T cells could be prevented by the addition of interleukin 2, which restored their ability to respond to their nominal antigen. Our data therefore suggest that HIV-1 variants can induce a state of anergy in HIV-specific CD4+ CTLs. Such a mechanism may allow a viral variant to not only escape the CTL response but also facilitate the persistence of other viral strains that may otherwise be recognized and eliminated by HIV-specific CTLs.

scholarly journals Programmed death-1 expression on HIV-1-specific CD8+ T cells is shaped by epitope specificity, T-cell receptor clonotype usage and antigen load

AIDS ◽  
2014 ◽  
Vol 28 (14) ◽  
pp. 2007-2021 ◽  
Author(s):  
Henrik N. Kløverpris ◽  
Reuben McGregor ◽  
James E. McLaren ◽  
Kristin Ladell ◽  
Anette Stryhn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
Epitope Specificity ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Hiv 1

scholarly journals The Pathway To Establishing HIV Latency Is Critical to How Latency Is Maintained and Reversed

2018 ◽  
Vol 92 (13) ◽  
pp. e02225-17 ◽  
Author(s):  
Simin D. Rezaei ◽  
Hao K. Lu ◽  
J. Judy Chang ◽  
Ajantha Rhodes ◽  
Sharon R. Lewin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Egfp Expression ◽  
Hiv Latency ◽  
Latently Infected ◽  
Infected Cells ◽  
Virus Expression

ABSTRACTHIV infection requires lifelong antiretroviral therapy because of the persistence of latently infected CD4+T cells. The induction of virus expression from latently infected cells occurs following T cell receptor (TCR) activation, but not all latently infected cells respond to TCR stimulation. We compared two models of latently infected cells using an enhanced green fluorescent protein (EGFP) reporter virus to infect CCL19-treated resting CD4+(rCD4+) T cells (preactivation latency) or activated CD4+T cells that returned to a resting state (postactivation latency). We isolated latently infected cells by sorting for EGFP-negative (EGFP−) cells after infection. These cells were cultured with antivirals and stimulated with anti-CD3/anti-CD28, mitogens, and latency-reversing agents (LRAs) and cocultured with monocytes and anti-CD3. Spontaneous EGFP expression was more frequent in postactivation than in preactivation latency. Stimulation of latently infected cells with monocytes/anti-CD3 resulted in an increase in EGFP expression compared to that for unstimulated controls using the preactivation latency model but led to a reduction in EGFP expression in the postactivation latency model. The reduced EGFP expression was not associated with reductions in the levels of viral DNA or T cell proliferation but depended on direct contact between monocytes and T cells. Monocytes added to the postactivation latency model during the establishment of latency reduced spontaneous virus expression, suggesting that monocyte-T cell interactions at an early time point postinfection can maintain HIV latency. This direct comparison of pre- and postactivation latency suggests that effective strategies needed to reverse latency will depend on how latency is established.IMPORTANCEOne strategy being evaluated to eliminate latently infected cells that persist in HIV-infected individuals on antiretroviral therapy (ART) is to activate HIV expression or production with the goal of inducing virus-mediated cytolysis or immune-mediated clearance of infected cells. The gold standard for the activation of latent virus is T cell receptor stimulation with anti-CD3/anti-CD28. However, this stimulus activates only a small proportion of latently infected cells. We show clear differences in the responses of latently infected cells to activating stimuli based on how latent infection is established, an observation that may potentially explain the persistence of noninduced intact proviruses in HIV-infected individuals on ART.

Generation of HIV-1-specific T cells by electroporation of T-cell receptor RNA

AIDS ◽  
2008 ◽  
Vol 22 (13) ◽  
pp. 1577-1582 ◽  
Author(s):  
Christian Hofmann ◽  
Thomas Harrer ◽  
Verena Kubesch ◽  
Katja Maurer ◽  
Karin J Metzner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Hiv 1

scholarly journals Induction of Fas Ligand Expression by HIV Involves the Interaction of Nef with the T Cell Receptor ζ Chain

1999 ◽  
Vol 189 (9) ◽  
pp. 1489-1496 ◽  
Author(s):  
Xiao-Ning Xu ◽  
Bernd Laffert ◽  
Gavin R. Screaton ◽  
Michael Kraft ◽  
Dietlinde Wolf ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Molecular Mechanism ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Fas Ligand ◽  
Cell Receptor ◽  
Fasl Expression ◽  
Hiv 1

During HIV/SIV infection, there is widespread programmed cell death in infected and, perhaps more importantly, uninfected cells. Much of this apoptosis is mediated by Fas–Fas ligand (FasL) interactions. Previously we demonstrated in macaques that induction of FasL expression and apoptotic cell death of both CD4+ and CD8+ T cells by SIV is dependent on a functional nef gene. However, the molecular mechanism whereby HIV-1 induces the expression of FasL remained poorly understood. Here we report a direct association of HIV-1 Nef with the ζ chain of the T cell receptor (TCR) complex and the requirement of both proteins for HIV-mediated upregulation of FasL. Expression of FasL through Nef depended upon the integrity of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the TCR ζ chain. Conformation for the importance of ζ for Nef-mediated signaling in T cells came from an independent finding. A single ITAM motif of ζ but not CD3ε was both required and sufficient to promote activation and binding of the Nef-associated kinase (NAK/p62). Our data imply that Nef can form a signaling complex with the TCR, which bypasses the requirement of antigen to initiate T cell activation and subsequently upregulation of FasL expression. Thus, our study may provide critical insights into the molecular mechanism whereby the HIV-1 accessory protein Nef contributes to the pathogenesis of HIV.

scholarly journals Gene transcription in differentiating immature T cell receptor(neg) thymocytes resembles antigen-activated mature T cells.

1993 ◽  
Vol 178 (4) ◽  
pp. 1139-1149 ◽  
Author(s):  
J C Zúñiga-Pflücker ◽  
H L Schwartz ◽  
M J Lenardo
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Intercellular Adhesion Molecule ◽  
Brdu Incorporation ◽  
Nuclear Factor ◽  
Nf Kappa B ◽  
Activated T Cells ◽  
Heat Stable Antigen

Early in ontogeny thymocytes have a surface marker phenotype that resembles activated mature T cells but they lack expression of the T cell receptor (TCR) complex. We have made preparations of day 14/15 triple negative fetal thymocytes that exhibit the activated T lymphocyte markers CD25, intercellular adhesion molecule 1, Ly-6A/E, CD44, and heat stable antigen and are rapidly proliferating as evidenced by flow cytometric examination of BrdU incorporation. We found that binding activities of the gene regulators nuclear factor (NF)-kappa B, the NF-kappa B p50 homodimer complex, nuclear factor of activated T cells (NF-AT), oct-1, oct-2, activator protein 1 (AP-1), and serum response factor (SRF), are all present in these early thymocytes. Whereas the octamer factors and SRF persist during ontogeny, NF-kappa B, NF-AT, and AP-1 decrease and are undetectable in the adult thymus. Transfection of disaggregated thymocytes by electroporation or intact thymic lobes by gold-particle bombardment revealed that reporter constructs for NF-kappa B, NF-AT, AP-1, octamer factors and, to a small extent, the TCR-alpha enhancer were active in early thymocyte development. We rigorously eliminated the possibility that these transcriptional events were due to minor populations of TCR+ cells by showing that these reporter constructs were also active in recombinase activating gene (RAG)-/- thymocytes that are incapable of completing TCR gene rearrangement, and predominantly contain cells that have an activated phenotype. Thus, transcriptional events that are usually triggered by antigen stimulation in mature T cells take place early in thymic ontogeny in the absence of the TCR. Our analysis suggests that there are striking regulatory similarities but also important differences between the activation processes that take place in antigen-stimulated mature T cells and thymic progenitor cells.

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