Cyclosporin A sensitivity of the HIV‐1 long terminal repeat identifies distinct p56lck‐dependent pathways activated by CD4 triggering

Somma, M. M. Di; Majolini, M. Bernardetta; Burastero, Samuele E.; Telford, John L.; Baldari, Cosima T.

doi:10.1002/eji.1830260933

Cited by 12 publications

(7 citation statements)

References 54 publications

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“…The nuclear factor subsystem includes nuclear factors of activated T cells (NFATs), transcriptional regulators that induce production of cytokines [60], [61]. We observe that NFATs are enhanced or activated at several levels within the host cell, by HIV-1 proteins Vpr, Tat, Nef and gp120, causing dysregulation of cytokine production [62]–[67]. Altered cytokine signals will then be received by cell-surface receptors, thus, completing a cycle of viral perturbation.…”

Section: Resultsmentioning

confidence: 99%

Patterns of HIV-1 Protein Interaction Identify Perturbed Host-Cellular Subsystems

et al. 2010

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Human immunodeficiency virus type 1 (HIV-1) exploits a diverse array of host cell functions in order to replicate. This is mediated through a network of virus-host interactions. A variety of recent studies have catalogued this information. In particular the HIV-1, Human Protein Interaction Database (HHPID) has provided a unique depth of protein interaction detail. However, as a map of HIV-1 infection, the HHPID is problematic, as it contains curation error and redundancy; in addition, it is based on a heterogeneous set of experimental methods. Based on identifying shared patterns of HIV-host interaction, we have developed a novel methodology to delimit the core set of host-cellular functions and their associated perturbation from the HHPID. Initially, using biclustering, we identify 279 significant sets of host proteins that undergo the same types of interaction. The functional cohesiveness of these protein sets was validated using a human protein-protein interaction network, gene ontology annotation and sequence similarity. Next, using a distance measure, we group host protein sets and identify 37 distinct higher-level subsystems. We further demonstrate the biological significance of these subsystems by cross-referencing with global siRNA screens that have been used to detect host factors necessary for HIV-1 replication, and investigate the seemingly small intersect between these data sets. Our results highlight significant host-cell subsystems that are perturbed during the course of HIV-1 infection. Moreover, we characterise the patterns of interaction that contribute to these perturbations. Thus, our work disentangles the complex set of HIV-1-host protein interactions in the HHPID, reconciles these with siRNA screens and provides an accessible and interpretable map of infection.

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Section: Resultsmentioning

confidence: 99%

Patterns of HIV-1 Protein Interaction Identify Perturbed Host-Cellular Subsystems

et al. 2010

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“…Further complexity to be considered when using in vivo CD4-interacting reagents derives from the fact that two sets of NFAT binding sites were identified in the HIV-1 long terminal repeat (LTR) promoter, and CD4 engagement can result on the p56 lck kinase dependent activation of both cellular transcription factors and HIV-1 LTR [42]. Thus, a signaling trigger via CD4 can activate both the endogenous and the retroviral NFAT family of transcription factors, simultaneously inducing both T cell activation and increased transcription of the viral genome [43].…”

Section: ) Anti-cd4 Antibodies In Clinical Practice: Beyond Immune Smentioning

confidence: 99%

Protective versus pathogenic anti-CD4 immunity: insights from the study of natural resistance to HIV infection

et al. 2009

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HIV-1 exposure causes several dramatic unbalances in the immune system homeostasis. Here, we will focus on the paradox whereby CD4 specific autoimmune responses, which are expected to contribute to the catastrophic loss of most part of the T helper lymphocyte subset in infected patients, may display the characteristics of an unconventional protective immunity in individuals naturally resistant to HIV-1 infection. Reference to differences in fine epitope mapping of these two oppositely polarized outcomes will be presented, with particular reference to partially or totally CD4-gp120 complex-specific antibodies. The fine tuning of the anti-self immune response to the HIV-1 receptor may determine whether viral exposure will result in infection or, alternatively, protective immunity.Along this line, an efficacious anti-HIV strategy can rely on the active (i.e., through immunization) or passive targeting of cryptic epitopes of the CD4-gp120 complex, including those harboured within the CD4 molecule. Such epitopes are expected to be safe from genetic drift and thus allow for broad spectrum of efficacy. Moreover, since these epitopes are not routinely exposed in uninfected individuals, they are expected to become targets of neutralizing antibodies or other specifically designed molecules only after viral exposure, with a predictable low impact in terms of potentially harmful anti-CD4 self-reactivity.The experimentum naturae of naturally resistant individuals indicates a strategy to design innovative strategies to neutralize HIV-1 by acting on the sharp edge between harmful and protective self-reactivity.

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“…This view is supported by the fact that TCR and CD4 share a wide array of common signaling mediators all of which are targets or the early tyrosine phosphorylation cascade [6][7][8][9][10][11][12]. The data show that surface expression of the TCR/CD3 complex is a prerequisite for productive CD4 signaling, suggesting that the signaling machinery of the TCR is promiscuously used by CD4.…”

Section: Discussionmentioning

confidence: 97%

Obligatory cross-talk with the tyrosine kinases assembled with the TCR/CD3 complex in CD4 signal transduction

et al. 1999

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Dissection of the CD4 signal transduction pathway has revealed striking similarities with the TCR/CD3 pathway. Furthermore, downstream signaling by CD4 is impaired in cells lacking surface TCR, suggesting a role for the TCR/CD3 complex in CD4 signal transduction. We have investigated the molecular basis for the dependence of CD4 signaling on TCR/CD3 expression. Using the phosphotyrosine binding domains of the Shc adaptor and the Fyn kinase, which both participate in CD4 signaling, as baits, we show that CD4 induces tyrosine phosphorylation of a subset of the proteins phosphorylated in response to TCR/CD3 engagement. The phosphoprotein patterns were dramatically altered in cells defective for TCR/CD3 expression, and were recoverable by reconstitution of correctly assembled TCR, suggesting that CD4 uses TCR/CD3-associated tyrosine kinases to signal. Among the tyrosine kinases associated with the resting TCR/CD3 complex, only Fyn is activated following CD4 engagement. The failure of Fyn to become phosphorylated in cells defective for TCR expression underlines the unique role of TCR/CD3 associated Fyn in CD4 signal transduction. While no calcium mobilization was measurable in cells defective for TCR/CD3 expression in response to CD4 engagement, the Ras/MAP kinase pathway could be partially activated. Thus, CD4 activates at least two signaling pathways, and tyrosine kinases associated with the TCR/CD3 complex are key components of one of these pathways.

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Cyclosporin A sensitivity of the HIV‐1 long terminal repeat identifies distinct p56lck‐dependent pathways activated by CD4 triggering

Cited by 12 publications

References 54 publications

Patterns of HIV-1 Protein Interaction Identify Perturbed Host-Cellular Subsystems

Patterns of HIV-1 Protein Interaction Identify Perturbed Host-Cellular Subsystems

Protective versus pathogenic anti-CD4 immunity: insights from the study of natural resistance to HIV infection

Obligatory cross-talk with the tyrosine kinases assembled with the TCR/CD3 complex in CD4 signal transduction

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