The Us3 Protein of Herpes Simplex Virus 1 Inhibits T Cell Signaling by Confining Linker for Activation of T Cells (LAT) Activation via TRAF6 Protein

Yang, Yonggang; Wu, Songfang; Wang, Yu; Pan, Shuang; Lan, Bei; Liu, Yaohui; Zhang, Liming; Leng, Qian-Li; Chen, Da; Zhang, Cuizhu; He, Bin; Cao, Youjia

doi:10.1074/jbc.m115.646422

Cited by 16 publications

(12 citation statements)

References 49 publications

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“…A similar effect was observed with other HSV glycoproteins, namely, gB, gH, gI, and gL in the same study [208]. A recent report suggests that impaired T-cell activation would also be mediated by HSV U s 3 protein interference with T-cell receptor signaling, specifically by altering linker for activation of T cells (LAT1) within these cells [209]. Importantly, infection of T cells (other than Jurkat cells) requires the presence of antigen-presenting cells for efficient virus transfer, a process termed virological synapse.…”

Section: Evasion Of T Cell Immunitysupporting

confidence: 78%

Immune Evasion by Herpes Simplex Viruses

Retamal-Díaz¹,

Tognarelli²,

Kalergis³

et al. 2016

Herpesviridae

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Infection with herpes simplex viruses type HSV-and type HSV-is extremely frequent in the human population, as well as recurrent reactivations due to lifelong infection. Infection and persistence of HSVs within healthy individuals likely results as a consequence of numerous molecular determinants evolved by these pathogens to escape both immediate and long-term host antiviral mechanisms. Indeed, HSVs harbor an arsenal of proteins that confer them stealth by negatively modulating immune function. Consequently, these viruses perpetuate within the host, altogether silently shedding onto other individuals. In this chapter, we discuss HSV determinants that interfere with cellular antiviral factors, as well as viral determinants that hamper innate and adaptive immune components intended to control such microbes. The identification of HSV evasion molecules that modulate the immune system, as well as the understanding of their mechanisms of action, should facilitate the design of novel prophylactic and therapeutic strategies to overcome infection and disease elicited by these viruses. This chapter is intended to provide an overview of the evasion mechanisms evolved by herpes simplex viruses to escape numerous host antiviral mediators.

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Section: Evasion Of T Cell Immunitysupporting

confidence: 78%

Immune Evasion by Herpes Simplex Viruses

Retamal-Díaz¹,

Tognarelli²,

Kalergis³

et al. 2016

Herpesviridae

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“…Because of defects in those pathways in cancer cells, mutations in many of these genes endow oncolytic activity to HSV [3]. Type 1 IFN production and its signaling pathway is key to antiviral innate immunity and thus HSV targets multiple steps in the pathway: (i) TLR signaling pathway; TLR3 and TLR2 signaling to TRAF6 are inhibited by Us3 [53], TRAF3 is inhibited by UL36 deubiquitinase [15], MyD88 and NF-kB subunits P50 and P65 are inhibited by ICP0 [54], nuclear translocation of NF-kB is inhibited by UL42 and Us3 [55,56], and ICP27 blocks NF-kB by binding to IkBα [57]. (ii) RIG-I-like receptor (RLR) signaling pathway; Us11 binds to PACT, RIG-I and MDA-5 to inhibit interaction with MAVS [58,59*], γ34.5 binds to TBK1 and inhibits IRF3 phosphorylation [60*], as does VP24 [61], Us3 hyper-phosphorylation of IRF3 blocks activation [62], ICP0 inhibits IRF3 translocation to the nucleus [63], and VP16 interferes with IRF3-CBP complex to inhibit transcription [15].…”

Section: Hsv Evasion Of Host Antiviral Responsesmentioning

confidence: 99%

“…Us3 interrupts TCR signaling by inhibiting the linker for activation of T cells (LAT) [53]. In T cells, HSV inhibits NF-κB activation and synthesis of pro-inflammatory cytokines like IL-2 and TNF-α, while activating STAT3 and the MAPK p38 and JNK pathways, and IL-10 synthesis [75].…”

Section: Hsv Evasion Of Host Antiviral Responsesmentioning

confidence: 99%

Oncolytic herpes simplex virus interactions with the host immune system

Saha

Wakimoto

Rabkin

2016

Current Opinion in Virology

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Oncolytic viruses (OVs), like oncolytic herpes simplex virus (oHSV), are genetically engineered to selectively replicate in and kill cancer cells, while sparing normal cells. Initial OV infection, cell death, and subsequent OV propagation within the tumor microenvironment leads to a cascade of host responses (innate and adaptive), reflective of natural anti-viral immune responses. These host-virus interactions are critical to the balance between OV activities, anti-viral immune responses limiting OV, and induction of anti-tumor immunity. The host response against oHSV is complex, multifaceted, and modulated by the tumor microenvironment and immunosuppression. As a successful pathogen, HSV has multiple mechanisms to evade such host responses. In this review, we will discuss these mechanisms and HSV evasion, and how they impact oHSV therapy.

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“…The earliest sign of immune exhaustion is a decrease in immune cells' capacity to secrete IFN-γ and IL-2 [8,22,23]. Yang et al showed that the Us3 protein, which is expressed by HHV-1, inhibits T-cell activation and other immune responses [24].…”

Section: Discussionmentioning

confidence: 99%

ThymicPeptides Reverse Immune Exhaustion in Patients with Reactivated Human Alphaherpesvirus1 Infections

Hymos

Grywalska

Klatka

et al. 2020

IJMS

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Recurrent infection with human alphaherpesvirus 1 (HHV-1) may be associated with immune exhaustion that impairs virus elimination. Thymic peptides enhance immune function and thus could overcome immune exhaustion. In this study, we investigated whether reactivation of herpes infections was associated with immune exhaustion. Moreover, we examined the impact of treatment with thymostimulin on the expression of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) on T and B lymphocytes in patients suffering from recurrent HHV-1 reactivation. We also assessed the effector function of peripheral blood mononuclear cells (PBMCs) after stimulation with thymic peptides. We enrolled 50 women with reactivated HHV-1 infections and healthy volunteers. We measured the expression of various activation and exhaustion markers on the surface of PBMCs using flow cytometry. In ex vivo experiments, we measured the secretion of inflammatory cytokines by PBMCs cultured with thymostimulin. Compared with controls, patients with reactivated HHV-1 infections had increased percentages of CD3+ co-expressing CD25, an activation marker (p < 0.001). Moreover, these patients had increased percentages of CD4+ and CD8+ cells co-expressing the inhibitory markers PD-1 and PD-L1. In cultures of PBMCs from the patients, thymostimulin increased the secretion of interferon gamma (p < 0.001) and interleukin (IL)-2 (p = 0.023), but not IL-4 or IL-10.Two-month thymostimulin therapy resulted in no reactivation of HHV-1 infection during this period and the reduction of PD-1 and PD-L1 expression on the surface of T and B lymphocytes (p < 0.001). In conclusion, reactivation of herpes infection is associated with immune exhaustion, which could be reversed by treatment with thymic peptides.

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The Us3 Protein of Herpes Simplex Virus 1 Inhibits T Cell Signaling by Confining Linker for Activation of T Cells (LAT) Activation via TRAF6 Protein

Cited by 16 publications

References 49 publications

Immune Evasion by Herpes Simplex Viruses

Immune Evasion by Herpes Simplex Viruses

Oncolytic herpes simplex virus interactions with the host immune system

ThymicPeptides Reverse Immune Exhaustion in Patients with Reactivated Human Alphaherpesvirus1 Infections

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