Binding of Herpes Simplex Virus Glycoprotein B (gB) to Paired Immunoglobulin-Like Type 2 Receptor α Depends on Specific Sialylated O-Linked Glycans on gB

ABSTRACT Paired immunoglobulin-like type 2 receptor α (PILRα) is an inhibitory receptor expressed on both hematopoietic and nonhematopoietic cells. Its binding to a cellular ligand, CD99, depends on the presence of sialylated O-linked glycans on CD99. Glycoprotein B (gB) of herpes simplex virus type 1 (HSV-1) binds to PILRα, and this association is involved in HSV-1 infection. Here, we found that the presence of sialylated O-glycans on gB is required for gB to associate with PILRα. Furthermore, we identified two threonine residues on gB that are essential for the addition of the principal O-glycans acquired by gB and that are also essential for the binding of PILRα to gB.

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Multiple Peptides Homologous to Herpes Simplex Virus Type 1 Glycoprotein B Inhibit Viral Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00793-08 ◽

2008 ◽

Vol 53 (3) ◽

pp. 987-996 ◽

Cited By ~ 33

Author(s):

Radeekorn Akkarawongsa ◽

Nina E. Pocaro ◽

Gary Case ◽

Aaron W. Kolb ◽

Curtis R. Brandt

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Viral Entry ◽

Herpes Simplex Virus Type ◽

Glycoprotein B ◽

Induced Mutations ◽

Simplex Virus ◽

Hsv 1

ABSTRACT The 773-residue ectodomain of the herpes simplex virus type 1 (HSV-1) glycoprotein B (gB) has been resistant to the use of mutagenic strategies because the majority of the induced mutations result in defective proteins. As an alternative strategy for the identification of functionally important regions and novel inhibitors of infection, we prepared a library of overlapping peptides homologous to the ectodomain of gB and screened for the ability of the peptides to block infection. Seven of 138 15-mer peptides inhibited infection by more than 50% at a concentration of 100 μM. Three peptides (gB94, gB122, and gB131) with 50% effective concentrations (EC50s) below 20 μM were selected for further studies. The gB131 peptide (residues 681 to 695 in HSV-1 gB [gB-1]) was a specific entry inhibitor (EC50, ∼12 μM). The gB122 peptide (residues 636 to 650 in gB-1) blocked viral entry (EC50, ∼18 μM), protected cells from infection (EC50, ∼72 μM), and inactivated virions in solution (EC50, ∼138 μM). We were unable to discern the step or steps inhibited by the gB94 peptide, which is homologous to residues 496 to 510 in gB-1. Substitution of a tyrosine in the gB122 peptide (Y640 in full-length gB-1) reduced the antiviral activity eightfold, suggesting that this residue is critical for inhibition. This peptide-based strategy could lead to the identification of functionally important regions of gB or other membrane proteins and identify novel inhibitors of HSV-1 entry.

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

Vaccines ◽

10.3390/vaccines8030478 ◽

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.

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

BioMed Research International ◽

10.1155/2016/2630865 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 5

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.

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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

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029600700406 ◽

1996 ◽

Vol 7 (4) ◽

pp. 209-212 ◽

Cited By ~ 1

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.

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.764861 ◽

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.

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Herpes simplex virus type 1 glycoprotein B sorting in hippocampal neurons

Journal of General Virology ◽

10.1099/vir.0.19279-0 ◽

2003 ◽

Vol 84 (10) ◽

pp. 2613-2624 ◽

Cited By ~ 9

Author(s):

Corinne Potel ◽

Karin Kaelin ◽

Lydia Danglot ◽

Antoine Triller ◽

Christian Vannier ◽

...

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Hippocampal Neurons ◽

Cytoplasmic Tail ◽

Glycoprotein B ◽

Simplex Virus ◽

Hsv 1

Herpes simplex virus type 1 (HSV-1) is a neuroinvasive human pathogen that spreads in the nervous system in functionally connected neurons. Determining how HSV-1 components are sorted in neurons is critical to elucidate the mechanisms of virus neuroinvasion. By using recombinant viruses expressing glycoprotein B (gB) tagged with green fluorescent protein (GFP), the subcellular localization of this envelope protein was visualized in infected hippocampal neurons in culture. Results obtained using a fully infectious recombinant virus containing GFP inserted into the ectodomain of gB support the view that capsids and gB are transported separately in neuron processes. Moreover, they show that during infection gB is sorted to the dendritic tree and the axons of polarized hippocampal neurons. However, GFP insertion into the cytoplasmic tail of gB impaired the maturation of the resulting fusion protein and caused its retention in the endoplasmic reticulum. The defective protein did not gain access to axons of infected neurons. These results suggest that the cytoplasmic tail of gB plays a role in maturation and transport and subsequently in axonal sorting in differentiated hippocampal neurons.

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