HVEM and Nectin-1 Are the Major Mediators of Herpes Simplex Virus 1 (HSV-1) Entry into Human Conjunctival Epithelium

Akhtar, Jihan; Tiwari, Vaibhav; Oh, Myounghak; Kovács, Mária; Jani, Aarti; Kovács, S. Krisztián; Vályi-Nagy, Tibor; Shukla, Deepak

doi:10.1167/iovs.08-1807

Cited by 66 publications

(69 citation statements)

References 28 publications

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“…40,41 Cells infected with HSV-1 strain K26GFP exhibit punctate nuclear fluorescence at early times in the replication cycle and at later times during infection, a generalized cytoplasmic and nuclear fluorescence, including fluorescence at the cell membranes can be observed. 40 K26GFP was shown to grow wt virus as well in cell culture.…”

Section: Virusesmentioning

confidence: 99%

Identification of virus resistant tumor cell subpopulations in three-dimensional uveal melanoma cultures

et al. 2009

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To better understand melanoma resistance to herpes simplex virus type 1 (HSV-1)-mediated oncolysis, traditional two-dimensional (2D) cultures and extracellular matrix (ECM) containing three-dimensional (3D) cultures of OCM1 and C918 uveal melanoma cells were infected with an HSV-1 strain that expresses the green fluorescent protein (GFP) marker during replication. Although 2D cultures were completely destroyed within a few days of HSV-1 inoculation, viable GFP-negative tumor cells remained detectable in 3D cultures for several weeks. Tumor cells with increased resistance to HSV-1 included cells that formed vasculogenic mimicry patterns and multicellular spheroids and cells that invaded Matrigel individually. Mechanisms of tumor resistance against HSV-1 in the 3D environment included impaired virus spread in the ECM and ECM-mediated inhibition of viral replication after viral entry into tumor cells. Observations also suggested that HSV-1 established quiescent infection in some tumor cells present in multicellular spheroids and that this could revert to productive viral infection when the tumor growth pattern changed. These findings indicate that 3D tumor cell cultures can be used to identify distinct tumor cell populations with increased resistance to HSV-1 and to explore mechanisms of ECM-mediated tumor resistance to oncolytic virotherapy.

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Section: Virusesmentioning

confidence: 99%

Identification of virus resistant tumor cell subpopulations in three-dimensional uveal melanoma cultures

et al. 2009

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“…Many known protein receptors for HSV-1 entry can be blocked by antibodies, which in turn, blocks viral entry [157,169]. Similar to those receptors, we also found that pAbs against synedecan-1 and syndecan-2 block entry.…”

Section: Discussionsupporting

confidence: 75%

“…However, high affinity interactions (accompanied by conformation changes) may not be blocked by antibodies and therefore, the net effect by combining the antibodies may not be significantly higher than the individual effects. This may be a reason why a near complete blocking of HSV-1 infection by antibodies has been extremely rare even when all gD receptors were blocked [157,169]. Our results, nevertheless, highlight that syndecan-1 and syndecan-2 both play a critical role during HSV-1 entry and that the two HSPGs show detectable differences in their abilities to facilitate infection.…”

Section: Discussionmentioning

confidence: 66%

“…Since the downregulation of syndecan-1 and syndecan-2 reduced HSV-1 entry, we wanted to determine whether a similar decrease in HSV-1 plaque formation and spread in HeLa cells is also observed after syndecan-1 and syndecan-2 downregulation by siRNA transfection. To this end, a standard plaque assay was performed [157]. As shown in Figure 11a, there was a clear and significant reduction in the number of plaques formed in HeLa cells transfected with syndecan-1-and syndecan-2-specific siRNAs compared with mock treated or scrambled siRNA-transfected cells.…”

Section: Syndecan-1 and Syndecan-2 Downregulation In Hela Cellsmentioning

confidence: 99%

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Investigations on molecular mechanisms of epithelial cell stress responses

Bacsa¹

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“…In addition, it has been reported that HVEM on nonhematopoietic cells, including mucosal epithelial cells, promotes antipathogen inflammation related to a Th17-type response (31,32,36). Although the cornea and palpebral conjunctiva are known to express HVEM (37,38), it remains unknown whether HVEM is expressed in the retina and uvea (i.e., target tissues in EAU), and if so, whether HVEM in these tissues plays any role in the pathogenesis of EAU. To address this question, we first examined HVEM expression in eye tissues, including the retina and uvea, and found positive staining by Western blot analysis, even though the level of expression was much lower than in the thymus (Supplemental Fig.…”

Section: Hvem On Nonhematopoietic Cells In Dispensable For Eau Pathogmentioning

confidence: 99%

Pathogenic Function of Herpesvirus Entry Mediator in Experimental Autoimmune Uveitis by Induction of Th1- and Th17-Type T Cell Responses

Sakoda

Nagai

Murata

et al. 2016

The Journal of Immunology

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Herpesvirus entry mediator (HVEM), a member of the TNFR superfamily, serves as a unique molecular switch to mediate both stimulatory and inhibitory cosignals, depending on its functions as a receptor or ligand interacting with multiple binding partners. In this study, we explored the cosignaling functions of HVEM in experimental autoimmune uveitis (EAU), a mouse model resembling human autoimmune uveitis conditions such as ocular sarcoidosis and Behcet disease. Our studies revealed that EAU severity significantly decreased in HVEM-knockout mice compared with wild-type mice, suggesting that stimulatory cosignals from the HVEM receptor are predominant in EAU. Further studies elucidated that the HVEM cosignal plays an important role in the induction of both Th1- and Th17-type pathogenic T cells in EAU, including differentiation of IL-17–producing αβ+γδ− conventional CD4+ T cells. Mice lacking lymphotoxin-like, inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT), B- and T-lymphocyte attenuator (BTLA) or both LIGHT and BTLA are also less susceptible to EAU, indicating that LIGHT–HVEM and BTLA–HVEM interactions, two major molecular pathways mediating HVEM functions, are both important in determining EAU pathogenesis. Finally, blocking HVEM cosignals by antagonistic anti-HVEM Abs ameliorated EAU. Taken together, our studies revealed a novel function of the HVEM cosignaling molecule and its ligands in EAU pathogenesis through the induction of Th1- and Th17-type T cell responses and suggested that HVEM-related molecular pathways can be therapeutic targets in autoimmune uveitis.

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HVEM and Nectin-1 Are the Major Mediators of Herpes Simplex Virus 1 (HSV-1) Entry into Human Conjunctival Epithelium

Abstract: HSV-1 entry into HCjE cells is a pH-dependent process that is aided by targeted virus travel on filopodia. HCjE cells express all three major entry receptors, with nectin-1 and HVEM playing the predominant role in mediating entry.

Cited by 66 publications

References 28 publications

Identification of virus resistant tumor cell subpopulations in three-dimensional uveal melanoma cultures

Identification of virus resistant tumor cell subpopulations in three-dimensional uveal melanoma cultures

Investigations on molecular mechanisms of epithelial cell stress responses

Pathogenic Function of Herpesvirus Entry Mediator in Experimental Autoimmune Uveitis by Induction of Th1- and Th17-Type T Cell Responses

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