scholarly journals Pharmacological Inhibition of IRE-1 Alpha Activity in Herpes Simplex Virus Type 1 and Type 2-Infected Dendritic Cells Enhances T Cell Activation

2022 ◽  
Vol 12 ◽  
Author(s):  
Eduardo I. Tognarelli ◽  
Angello Retamal-Díaz ◽  
Mónica A. Farías ◽  
Luisa F. Duarte ◽  
Tomás F. Palomino ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections are life-long and highly prevalent in the human population. These viruses persist in the host, eliciting either symptomatic or asymptomatic infections that may occur sporadically or in a recurrent manner through viral reactivations. Clinical manifestations due to symptomatic infection may be mild such as orofacial lesions, but may also translate into more severe diseases, such as ocular infections that may lead to blindness and life-threatening encephalitis. A key feature of herpes simplex viruses (HSVs) is that they have evolved molecular determinants that hamper numerous components of the host’s antiviral innate and adaptive immune system. Importantly, HSVs infect and negatively modulate the function of dendritic cells (DCs), by inhibiting their T cell-activating capacity and eliciting their apoptosis after infection. Previously, we reported that HSV-2 activates the splicing of the mRNA of XBP1, which is related to the activity of the unfolded protein response (UPR) factor Inositol-Requiring Enzyme 1 alpha (IRE-1α). Here, we sought to evaluate if the activation of the IRE-1α pathway in DCs upon HSV infection may be related to impaired DC function after infection with HSV-1 or HSV-2. Interestingly, the pharmacological inhibition of the endonuclease activity of IRE-1α in HSV-1- and HSV-2-infected DCs significantly reduced apoptosis in these cells and enhanced their capacity to migrate to lymph nodes and activate virus-specific CD4+ and CD8+ T cells. These findings suggest that the activation of the IRE-1α-dependent UPR pathway in HSV-infected DCs may play a significant role in the negative effects that these viruses exert over these cells and that the modulation of this signaling pathway may be relevant for enhancing the function of DCs upon infection with HSVs.

scholarly journals CD4+ T-cell responses to herpes simplex virus type 2 (HSV-2) glycoprotein G are type specific and differ in symptomatic and asymptomatic HSV-2-infected individuals

2004 ◽  
Vol 85 (8) ◽  
pp. 2139-2147 ◽  
Author(s):  
Kristina Eriksson ◽  
Lars Bellner ◽  
Staffan Görander ◽  
Gun-Britt Löwhagen ◽  
Petra Tunbäck ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Mononuclear Cells ◽  
Glycoprotein G ◽  
Simplex Virus ◽  
Hsv 1

T-cell recognition of the secreted and membrane-bound portions of the herpes simplex virus type 2 (HSV-2) glycoprotein G (sgG-2 and mgG-2, respectively) was compared in symptomatic and asymptomatic HSV-2-infected individuals and in HSV-2-seronegative controls and the responses with HSV-1 glycoproteins C and E (gC-1 and gE-1) were compared. CD4+ T cells from HSV-2-infected individuals specifically recognized both sgG-2 and mgG-2, whereas HSV-1-infected and HSV-seronegative controls did not respond to these glycoproteins. The responses to gC-1 and gE-1, on the other hand, were not type specific, as blood mononuclear cells from both HSV-1- and HSV-2-infected individuals responded in vitro. There was an association between the status of the infection (symptomatic versus asymptomatic) and the CD4+ T-cell responsiveness. Symptomatic HSV-2-seropositive individuals responded with significantly lower Th1 cytokine production to sgG-2 and mgG-2 than did asymptomatic HSV-2-infected carriers, especially within the HSV-1-negative cohort. No differences in T-cell proliferation were observed between asymptomatic and symptomatic individuals. The results have implications for studies of HSV-2-specific CD4+ T-cell reactivity in general and for analysis of immunological differences between asymptomatic and symptomatic individuals in particular.

scholarly journals T Cell Receptor–γ/δ Cells Protect Mice from Herpes Simplex Virus Type 1–induced Lethal Encephalitis

1997 ◽  
Vol 185 (11) ◽  
pp. 1969-1975 ◽  
Author(s):  
Roger Sciammas ◽  
P. Kodukula ◽  
Q. Tang ◽  
R.L. Hendricks ◽  
J.A. Bluestone
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
T Cell Receptor ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Cell Receptor ◽  
Simplex Virus ◽  
Hsv 1

Increased numbers of T cell receptor (TCR)-γ/δ cells have been observed in animal models of influenza and sendai virus infections, as well as in patients infected with human immunodeficiency virus and herpes simplex virus type 1 (HSV-1). However, a direct role for TCR-γ/δ cells in protective immunity for pathogenic viral infection has not been demonstrated. To define the role of TCR-γ/δ cells in anti–HSV-1 immunity, TCR-α−/− mice treated with anti– TCR-γ/δ monoclonal antibodies or TCR-γ/δ × TCR-α/β double-deficient mice were infected with HSV-1 by footpad or ocular routes of infection. In both models of HSV-1 infection, TCR-γ/δ cells limited severe HSV-1–induced epithelial lesions and greatly reduced mortality by preventing the development of lethal viral encephalitis. The observed protection resulted from TCR-γ/δ cell–mediated arrest of both viral replication and neurovirulence. The demonstration that TCR-γ/δ cells play an important protective role in murine HSV-1 infections supports their potential contribution to the immune responses in human HSV-1 infection. Thus, this study demonstrates that TCR-γ/δ cells may play an important regulatory role in human HSV-1 infections.

scholarly journals In Vivo Ablation of CD11c-Positive Dendritic Cells Increases Susceptibility to Herpes Simplex Virus Type 1 Infection and Diminishes NK and T-Cell Responses

2006 ◽  
Vol 80 (8) ◽  
pp. 3985-3993 ◽  
Author(s):  
Sadik H. Kassim ◽  
Naveen K. Rajasagi ◽  
Xiangyi Zhao ◽  
Robert Chervenak ◽  
Stephen R. Jennings
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The precise role of each of the seven individual CD11c+ dendritic cell subsets (DCs) identified to date in the response to viral infections is not known. DCs serve as critical links between the innate and adaptive immune responses against many pathogens, including herpes simplex virus type 1 (HSV-1). The role of DCs as mediators of resistance to HSV-1 infection was investigated using CD11c-diphtheria toxin (DT) receptor-green fluorescent protein transgenic mice, in which DCs can be transiently depleted in vivo by treatment with low doses of DT. We show that ablation of DCs led to enhanced susceptibility to HSV-1 infection in the highly resistant C57BL/6 mouse strain. Specifically, we showed that the depletion of DCs led to increased viral spread into the nervous system, resulting in an increased rate of morbidity and mortality. Furthermore, we showed that ablation of DCs impaired the optimal activation of NK cells and CD4+ and CD8+ T cells in response to HSV-1. These data demonstrated that DCs were essential not only in the optimal activation of the acquired T-cell response to HSV-1 but also that DCs were crucial for innate resistance to HSV-1 infection.

scholarly journals Herpes Simplex Virus Type 2 Is More Difficult to Neutralize by Antibodies Than Herpes Simplex Virus Type 1

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 478
Author(s):  
Christiane Silke Heilingloh ◽  
Christopher Lull ◽  
Elissa Kleiser ◽  
Mira Alt ◽  
Leonie Schipper ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Vaccine Trial ◽  
Antibody Treatment ◽  
Simplex Virus ◽  
Hsv 1

Infections with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are a global health burden. Besides painful oral or genital lesions in otherwise healthy subjects, both viruses can cause devastating morbidity and mortality in immune-compromised and immune-immature individuals. The latter are particularly susceptible to a disseminated, life-threatening disease. Neutralizing antibodies (NAb) constitute a correlate of protection from disease, and are promising candidates for the prophylactic or therapeutic treatment of severe HSV infections. However, a clinical vaccine trial suggested that HSV-2 might be more resistant to NAbs than HSV-1. In the present study, we investigated the antiviral efficacy of the well-characterized humanized monoclonal antibody (mAb) hu2c against HSV-2, in a NOD/SCID immunodeficiency mouse model. Despite the fact that hu2c recognizes a fully conserved epitope and binds HSV-1 and HSV-2 glycoprotein B with equal affinity, it was much less effective against HSV-2 in vitro and in NOD/SCID mice. Although intravenous antibody treatment prolonged the survival of HSV-2-infected mice, complete protection from death was not achieved. Our data demonstrate that HSV-2 is more resistant to NAbs than HSV-1, even if the same antibody and antigen are concerned, making the development of a vaccine or therapeutic antibodies more challenging.

scholarly journals Infection of dendritic cells with herpes simplex virus type 1 induces rapid degradation of CYTIP, thereby modulating adhesion and migration

Blood ◽  
2011 ◽  
Vol 118 (1) ◽  
pp. 107-115 ◽  
Author(s):  
Alexandros A. Theodoridis ◽  
Christina Eich ◽  
Carl G. Figdor ◽  
Alexander Steinkasserer
Keyword(s):  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Lymphoid Tissues ◽  
Simplex Virus ◽  
Hsv 1

Abstract Immune responses require spatial and temporal coordinated interactions between different cell types within distinct microenvironments. This dynamic interplay depends on the competency of the involved cells, predominantly leukocytes, to actively migrate to defined sites of cellular encounters in various tissues. Because of their unique capacity to transport antigen from the periphery to secondary lymphoid tissues for the activation of naive T cells, dendritic cells (DCs) play a key role in the initiation and orchestration of adaptive immune responses. Therefore, pathogen-mediated interference with this process is a very effective way of immune evasion. CYTIP (cytohesin-interacting protein) is a key regulator of DC motility. It has previously been described to control LFA-1 deactivation and to regulate DC adherence. CYTIP expression is up-regulated during DC maturation, enabling their transition from the sessile to the motile state. Here, we demonstrate that on infection of human monocyte-derived DCs with herpes simplex virus type 1 (HSV-1), CYTIP is rapidly degraded and as a consequence β-2 integrins, predominantly LFA-1, are activated. Furthermore, we show that the impairment of migration in HSV-1-infected DCs is in part the result of this increased integrin-mediated adhesion. Thus, we propose a new mechanism of pathogen-interference with central aspects of leukocyte biology.

scholarly journals Interaction of ICP34.5 with Beclin 1 Modulates Herpes Simplex Virus Type 1 Pathogenesis through Control of CD4+ T-Cell Responses

2009 ◽  
Vol 83 (23) ◽  
pp. 12164-12171 ◽  
Author(s):  
David A. Leib ◽  
Diane E. Alexander ◽  
Douglas Cox ◽  
Jiyi Yin ◽  
Thomas A. Ferguson
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Antigen Presentation ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Beclin 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Autophagy is an important component of host innate and adaptive immunity to viruses. It is critical for the degradation of intracellular pathogens and for promoting antigen presentation. Herpes simplex virus type 1 (HSV-1) infection induces an autophagy response, but this response is antagonized by the HSV-1 neurovirulence gene product, ICP34.5. This is due, in part, to its interaction with the essential autophagy protein Beclin 1 (Atg6) via the Beclin-binding domain (BBD) of ICP34.5. Using a recombinant virus lacking the BBD, we examined pathogenesis and immune responses using mouse models of infection. The BBD-deficient virus (Δ68H) replicated equivalently to its marker-rescued counterpart (Δ68HR) at early times but was cleared more rapidly than Δ68HR from all tissues at late times following corneal infection. In addition, the infection of the cornea with Δ68H induced less ocular disease than Δ68HR. These results suggested that Δ68H was attenuated due to its failure to control adaptive rather than innate immunity. In support of this idea, Δ68H stimulated a significantly stronger CD4+ T-cell-mediated delayed-type hypersensitivity response and resulted in significantly more production of gamma interferon and interleukin-2 from HSV-specific CD4+ T cells than Δ68HR. Taken together, these data suggest a role for the BBD of ICP34.5 in precluding autophagy-mediated class II antigen presentation, thereby enhancing the virulence and pathogenesis of HSV-1.

scholarly journals Herpes Simplex Virus Type 1 and Type 2 Infection Increases Atherosclerosis Risk: Evidence Based on a Meta-Analysis

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Yu peng Wu ◽  
Dan dan Sun ◽  
Yun Wang ◽  
Wen Liu ◽  
Jun Yang
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Subgroup Analysis ◽  
Meta Analysis ◽  
Simplex Virus ◽  
Hsv 1

Objective.The aim of our study was to evaluate the relation of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infection with the risk of atherosclerosis (AS).Methods.A systematic literature search was performed through three electronic databases. The pooled odds ratio (OR) and corresponding 95% confidence interval (CI) were used to assess the effect of HSV-1 and HSV-2 infection on AS risk.Results.17 studies were available for meta-analysis of HSV-1 infection and AS risk and seven studies for meta-analysis of HSV-2 infection and AS risk. Subjects exposed to HSV-1 infection exhibited an increased risk of AS (OR = 1.77; 95% CI: 1.40–2.23;P<0.001). And consistent elevated AS risks for HSV-1 positive subjects were found in all subgroup analysis of disease type, region, male proportion, and age. HSV-2 positive subjects demonstrated significantly increased AS risk (OR = 1.37; 95% CI: 1.13–1.67;P<0.005). In subgroup analysis, elevated AS risks were only observed in myocardial ischemia group, male proportion >60% group, and age ≤60-year-old group.Conclusion.Our meta-analysis indicated that HSV-1 and HSV-2 infection could increase the risk of contracting AS.

scholarly journals The FIAU Derivative (2′S)-2′-Deoxy-2′-C-Methyl-5-Iodouridine (SMIU) is a Novel, Less Cytotoxic and Potent anti-HSV and anti-VZV Agent

1996 ◽  
Vol 7 (4) ◽  
pp. 209-212 ◽  
Author(s):  
T. Kira ◽  
H. Awano ◽  
S. Shuto ◽  
A. Matsuda ◽  
M. Baba ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Varicella Zoster ◽  
Antiviral Activities ◽  
Simplex Virus ◽  
Hsv 1

In this study, the anti-herpetic activities of novel 2′-methyl nucleoside analogues which were substituted at the 5 position of the pyrimidine with a halogen were investigated. The 2′-fluoro-5-iodo-aracytosine (FIAC) congeners (2′S)-2′-deoxy-2′- C-methylcytidine which were substituted with Br or I at the 5 position (SMBC or SMIC); and 2′-fluoro-5-iodo-arauridine (FIAU) congeners (2′S)-2′-deoxy-2′-C-methyluridine which were substituted with Br or I at the 5 position (SMBU or SMIU), proved to have potent antiviral activities against herpes simplex virus type-1 (HSV-1) and varicella-zoster virus (VZV) but not against herpes simplex virus type-2 (HSV-2). SMIU has a higher selective index against HSV-1 than FIAU, and both SMIC and SMIU showed higher inhibitory effects against VZV replication than aciclovir. The four effective compounds were not inhibitory to a thymidine kinase (TK)-negative HSV-1 strain, and this result indicates that phosphorylation of the compounds by HSV or VZV-TK is necessary for the activation of these compounds.

scholarly journals Infection of mature dendritic cells with herpes simplex virus type 1 dramatically reduces lymphoid chemokine-mediated migration

2005 ◽  
Vol 86 (6) ◽  
pp. 1645-1657 ◽  
Author(s):  
Alexander T. Prechtel ◽  
Nadine M. Turza ◽  
Dieter J. Kobelt ◽  
Jutta I. Eisemann ◽  
Robert S. Coffin ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Antiviral Immune Response ◽  
Migration Assays ◽  
Simplex Virus ◽  
Hsv 1

Herpes simplex virus type 1 (HSV-1) is able to establish latency in infected individuals. In order to characterize potential new immune-escape mechanisms, mature dendritic cells (DCs) were infected with HSV-1 and total cellular RNA was isolated from infected and mock-infected populations at different time points. RNA profiling on Affymetrix Human Genome U133A arrays demonstrated a dramatic downregulation of the migration-mediating surface molecules CCR7 and CXCR4, an observation that was further confirmed by RT-PCR and fluorescence-activated cell sorting analyses. Furthermore, migration assays revealed that, upon infection of mature DCs, CCR7- and CXCR4-mediated migration towards the corresponding CCL19 and CXCL12 chemokine gradients was strongly reduced. It is noteworthy that the infection of immature DCs with HSV-1 prior to maturation led to a failure of CCR7 and CXCR4 upregulation during DC maturation and, as a consequence, also induced a block in their migratory capacity. Additional migration assays with a Δvhs mutant virus lacking the virion host shutoff (vhs) gene, which is known to degrade cellular mRNAs, suggested a vhs-independent mechanism. These results indicate that HSV-1-infected mature DCs are limited in their capacity to migrate to secondary lymphoid organs, the areas of antigen presentation and T-cell stimulation, thus inhibiting an antiviral immune response. This represents a novel, previously unrecognized mechanism for HSV-1 to escape the human immune system.

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