The Experts below are selected from a list of 975 Experts worldwide ranked by ideXlab platform
Roselyn J Eisenberg - One of the best experts on this subject based on the ideXlab platform.
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herpes simplex virus glycoprotein d interferes with binding of Herpesvirus Entry Mediator to its ligands through downregulation and direct competition
Journal of Virology, 2010Co-Authors: Katie M Stiles, Roselyn J Eisenberg, Gary H Cohen, Charles J Whitbeck, Huan Lou, Claude KrummenacherAbstract:To initiate membrane fusion and virus Entry, herpes simplex virus (HSV) gD binds to a cellular receptor such as Herpesvirus Entry Mediator (HVEM). HVEM is a tumor necrosis factor (TNF) receptor family member with four natural ligands that either stimulate (LIGHT and LTα) or inhibit (BTLA and CD160) T cell function. We hypothesized that the interaction of gD with HVEM affects the binding of natural ligands, thereby modulating the immune response during infection. Here, we investigated the effect that gD has on the interaction of HVEM with its natural ligands. First, HSV gD on virions or cells downregulates HVEM from the cell surface. Similarly, trans-interaction with BTLA or LIGHT also downregulates HVEM from the cell surface, suggesting that HSV may subvert a natural mechanism for regulating HVEM activity. Second, we showed that wild-type gD had the lowest affinity for HVEM compared with the four natural ligands. Moreover, gD directly competed for binding to HVEM with BTLA but not LTα or LIGHT, indicating the possibility that gD selectively controls HVEM signals. On the other hand, natural ligands influence the use of HVEM by HSV. For instance, soluble BTLA, LTα, and LIGHT inhibited the binding of wild-type gD to HVEM, and soluble BTLA and LTα blocked HSV infection of HVEM-expressing cells. Thus, gD is at the center of the interplay between HVEM and its ligands. It can interfere with HVEM function in two ways, by competing with the natural ligands and by downregulating HVEM from the cell surface.
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Herpes Simplex Virus Glycoprotein D Interferes with Binding of Herpesvirus Entry Mediator to Its Ligands through
2010Co-Authors: Direct Competition, Roselyn J Eisenberg, Claude KrummenacherAbstract:To initiate membrane fusion and virus Entry, herpes simplex virus (HSV) gD binds to a cellular receptor such as Herpesvirus Entry Mediator (HVEM). HVEM is a tumor necrosis factor (TNF) receptor family member with four natural ligands that either stimulate (LIGHT and LT) or inhibit (BTLA and CD160) T cell function. We hypothesized that the interaction of gD with HVEM affects the binding of natural ligands, thereby modulating the immune response during infection. Here, we investigated the effect that gD has on the interaction of HVEM with its natural ligands. First, HSV gD on virions or cells downregulates HVEM from the cell surface. Similarly, trans-interaction with BTLA or LIGHT also downregulates HVEM from the cell surface, suggesting that HSV may subvert a natural mechanism for regulating HVEM activity. Second, we showed that wild-type gD had the lowest affinity for HVEM compared with the four natural ligands. Moreover, gD directly competed for binding to HVEM with BTLA but not LT or LIGHT, indicating the possibility that gD selectively controls HVEM signals. On the other hand, natural ligands influence the use of HVEM by HSV. For instance, soluble BTLA, LT, and LIGHT inhibited the binding of wild-type gD to HVEM, and soluble BTLA and LT blocked HSV infection of HVEM-expressing cells. Thus, gD is at the center of the interplay between HVEM and its ligands. It can interfere with HVEM function in two ways, by competing with the natural ligands and by downregulating HVEM from the cell surface
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Targeting of antigen to the Herpesvirus Entry Mediator augments primary adaptive immune responses.
Nature medicine, 2008Co-Authors: Marcio O. Lasaro, Roselyn J Eisenberg, Gary H Cohen, J. Charles Whitbeck, Nia Tatsis, Scott E. Hensley, Shih-wen Lin, John J. Rux, E. John Wherry, Hildegund C.j. ErtlAbstract:Interactions between the Herpesvirus Entry Mediator (HVEM) and the B- and T-lymphocyte attenuator (BTLA) inhibit B and T cell activation. HVEM-BTLA interactions are blocked by herpes simplex virus (HSV) glycoprotein D (gD) through binding of its N-terminal domain to the BTLA binding site of HVEM. In this study, we inserted viral antigens into the C-terminal domain of gD and expressed these antigens with plasmid or E1-deleted (replication-defective) adenovirus vectors. Viral antigens fused to gD induced T and B cell responses to the antigen that were far more potent than those elicited by the same antigen expressed without gD. The immunopotentiating effect required binding of the gD chimeric protein to HVEM. Overall, the studies demonstrate that targeting of antigen to the BTLA binding site of HVEM augments the immunogenicity of vaccines.
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Nectin-1/HveC Mediates herpes simplex virus type 1 Entry into primary human sensory neurons and fibroblasts.
Journal of neurovirology, 2005Co-Authors: Scott A. Simpson, Claude Krummenacher, Gary H Cohen, Michael D. Manchak, Elizabeth Hager, J. Charles Whitbeck, Myron J. Levin, Curt R. Freed, Christine L. Wilcox, Roselyn J EisenbergAbstract:Immunocytochemistry detects nectin-1/HveC, nectin-2/HveB, and HVEM/HveA on the surface of sensory neurons and fibroblasts grown as primary cultures from human dorsal root ganglia. Viral Entry into these cultured cells was assayed by infection with a recombinant herpes simplex virus type 1 (HSV-1) expressing green fluorescent protein. Soluble, truncated nectin-1 polypeptide, as well as polyclonal and monoclonal antibodies against nectin-1, inhibited infection of neurons, whereas polypeptides and antibodies capable of inhibiting HSV-1 interaction with nectin-2 and Herpesvirus Entry Mediator (HVEM) failed to prevent infection of neuronal cells. These results demonstrate that nectin-1 is the primary receptor for HSV-1 Entry into human fetal neurons. Viral Entry into fibroblasts was also reduced by soluble nectin-1 but not by soluble HVEM. However, in contrast to the results obtained with neurons, antibodies against receptors failed to inhibit Entry into fibroblasts, indicating that unlike neurons, fibroblasts have multiple receptors or mechanisms for HSV-1 Entry.
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Comparative usage of Herpesvirus Entry Mediator A and nectin-1 by laboratory strains and clinical isolates of herpes simplex virus.
Virology, 2004Co-Authors: Claude Krummenacher, Gary H Cohen, Isabelle Baribaud, J. Charles Whitbeck, Frédéric Baribaud, Manuel Ponce De Leon, Roselyn J EisenbergAbstract:The Herpesvirus Entry Mediator A (HVEM/HveA) and nectin-1 (HveC/CD111) are two major receptors for herpes simplex virus (HSV). Although structurally unrelated, both receptors can independently mediate Entry of wild-type (wt) HSV-1 and HSV-2 by interacting with the viral envelope glycoprotein D (gD). Laboratory strains with defined mutations in gD (e.g. rid1) do not use HVEM but use nectin-2 (HveB/CD112) for Entry. The relative usage of HVEM and nectin-1 during HSV infection in vivo is not known. In the absence of a defined in vivo model, we used in vitro approaches to address this question. First, we screened HSV clinical isolates from various origins for receptor tropism and found that all used both HVEM and nectin-1. Second, we determined the numbers of surface receptors on various susceptible and resistant cell lines as well as on primary fibroblasts derived from an individual with cleft lip/palate ectodermal dysplasia (CLPED1). Although CLPED1 cells can only express a defective form of nectin-1, they allowed Entry of wild type and mutant HSV strains by usage of either HVEM or nectin-2. Finally, we compared the ability of HVEM and nectin-1 to mediate Entry when expressed at varying cell surface densities. Both receptors showed a direct relationship between the number of receptors and HSV susceptibility. Direct comparison of receptors suggests that nectin-1 is more efficient at promoting Entry than HVEM. Overall, our data suggest that both receptors play a role during HSV infection in vivo and that both are highly efficient even at low levels of expression.
Carl F. Ware - One of the best experts on this subject based on the ideXlab platform.
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a Herpesvirus Entry Mediator mutein with selective agonist action for the inhibitory receptor b and t lymphocyte attenuator
Journal of Biological Chemistry, 2017Co-Authors: John R Sedý, Paula S. Norris, Brian C. Ware, Olivia M Balmert, Wendell Smith, Ivana Nemcovicova, Brian R Miller, Dikran Aivazian, Carl F. WareAbstract:Abstract The human cytomegalovirus opening reading frame UL144 is an ortholog of the TNF receptor superfamily member, Herpesvirus Entry Mediator (HVEM; TNFRSF14). HVEM binds the TNF ligands, LIGHT and LTa; the immunoglobulin inhibitory receptor, B and T lymphocyte attenuator (BTLA); and the natural killer cell–activating receptor CD160. However, UL144 selectively binds BTLA, avoiding activation of inflammatory signaling initiated by CD160 in natural killer cells. BTLA and CD160 cross-compete for binding HVEM, but the structural basis for the ligand selectivity by UL144 and how it acts as an anti-inflammatory agonist remains unclear. Here, we modeled the UL144 structure and characterized its binding with BTLA. The UL144 structure was predicted to closely mimic the surface of HVEM, and we also found that both HVEM and UL144 bind a common epitope of BTLA, whether engaged in trans or in cis, that is shared with a BTLA antibody agonist. On the basis of the UL144 selectivity, we engineered a BTLA-selective HVEM protein to understand the basis for ligand selectivity and BTLA agonism to develop novel anti-inflammatory agonists. This HVEM mutein did not bind CD160 or TNF ligands but did bind BTLA with 10-fold stronger affinity than wild-type HVEM and retained potent inhibitory activity that reduced T-cell receptor, B-cell receptor, and interferon signaling in B cells. In conclusion, using a viral immune evasion strategy that shows broad immune-ablating activity, we have identified a novel anti-inflammatory BTLA-selective agonist.
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LIGHT Expression by Mucosal T Cells May Regulate IFN-! Expression in the Intestine1
2015Co-Authors: Offer Cohavy, Carl F. Ware, Jaclyn Zhou, Steve W. Granger, Stephan R. TarganAbstract:The TNF superfamily of cytokines play an important role in T cell activation and inflammation. Sustained expression of lym-photoxin-like inducible protein that competes with glycoprotein D for binding Herpesvirus Entry Mediator on T cells (LIGHT) (TNFSF14) causes a pathological intestinal inflammation when constitutively expressed by mouse T cells. In this study, we char-acterized LIGHT expression on activated human T cell subsets in vitro and demonstrated a direct proinflammatory effect on regulation of IFN-!. LIGHT was induced in memory CD45RO CD4 " T cells and by IFN-!-producing CD4 " T cells. Kinetic analysis indicated rapid induction of LIGHT by human lamina propria T cells, reaching maximal levels by 2–6 h, whereas peripheral blood or lymph node-derived T cells required 24 h. Further analysis of intestinal specimens from a 41 patient cohort by flow cytometry indicated membrane LIGHT induction to higher peak levels in lamina propria T cells from the small bowel or rectum but not colon, when compared with lymph node or peripheral blood. Independent stimulation of the LIGHT receptor, Herpesvirus Entry Mediator, induced IFN-! production in lamina propria T cells, while blocking LIGHT inhibited CD2-dependent induction of IFN-! synthesis, indicating a role for LIGHT in the regulation of IFN-! and as a putative Mediator of proinflam-matory T-T interactions in the intestinal mucosa. Taken together, these findings suggest LIGHT-Herpesvirus Entry Mediator mediated signaling as an important immune regulatory mechanism in mucosal inflammatory responses. The Journal of Immu-nology, 2004, 173: 251–258. T he TNFR ligand family has a critical signaling role inmammalian biology, especially in the development andregulation of the immune system (1), by controlling cel
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Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency
Journal of virology, 2013Co-Authors: Sariah J. Allen, Carl F. Ware, Antje Rhode-kurnow, Kevin R. Mott, Xianzhi Jiang, Dale Carpenter, J. Ignacio Rodriguez-barbosa, Clinton Jones, Steven L. Wechsler, Homayon GhiasiAbstract:Herpesvirus Entry Mediator (HVEM) is one of several cell surface proteins herpes simplex virus (HSV) uses for attachment/Entry. HVEM regulates cellular immune responses and can also increase cell survival. Interestingly, latency-associated transcript (LAT), the only viral gene consistently expressed during neuronal latency, enhances latency and reactivation by promoting cell survival and by helping the virus evade the host immune response. However, the mechanisms of these LAT activities are not well understood. We show here for the first time that one mechanism by which LAT enhances latency and reactivation appears to be by upregulating HVEM expression. HSV-1 latency/reactivation was significantly reduced in Hvem−/− mice, indicating that HVEM plays a significant role in HSV-1 latency/reactivation. Furthermore, LAT upregulated HVEM expression during latency in vivo and also when expressed in vitro in the absence of other viral factors. This study suggests a mechanism whereby LAT upregulates HVEM expression potentially through binding of two LAT small noncoding RNAs to the HVEM promoter and that the increased HVEM then leads to downregulation of immune responses in the latent microenvironment and increased survival of latently infected cells. Thus, one of the mechanisms by which LAT enhances latency/reactivation appears to be through increasing expression of HVEM.
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CD160 Activation by Herpesvirus Entry Mediator Augments Inflammatory Cytokine Production and Cytolytic Function by NK Cells
Journal of immunology (Baltimore Md. : 1950), 2013Co-Authors: John R Sedý, Paula S. Norris, Matthew G. Macauley, Ryan L. Bjordahl, Vasileios Bekiaris, Brian C. Ware, Nell S. Lurain, Chris A. Benedict, Carl F. WareAbstract:Lymphocyte activation is regulated by costimulatory and inhibitory receptors, of which both B and T lymphocyte attenuator (BTLA) and CD160 engage Herpesvirus Entry Mediator (HVEM). Notably, it remains unclear how HVEM functions with each of its ligands during immune responses. In this study, we show that HVEM specifically activates CD160 on effector NK cells challenged with virus-infected cells. Human CD56dim NK cells were costimulated specifically by HVEM but not by other receptors that share the HVEM ligands LIGHT, Lymphotoxin-α, or BTLA. HVEM enhanced human NK cell activation by type I IFN and IL-2, resulting in increased IFN-γ and TNF-α secretion, and tumor cell–expressed HVEM activated CD160 in a human NK cell line, causing rapid hyperphosphorylation of serine kinases ERK1/2 and AKT and enhanced cytolysis of target cells. In contrast, HVEM activation of BTLA reduced cytolysis of target cells. Together, our results demonstrate that HVEM functions as a regulator of immune function that activates NK cells via CD160 and limits lymphocyte-induced inflammation via association with BTLA.
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Selective blockade of Herpesvirus Entry Mediator-B and T lymphocyte attenuator pathway ameliorates acute graft-versus-host reaction.
Journal of Immunology, 2012Co-Authors: Nick D. Jones, Leo Buhler, Carl F. Ware, Yasushi Shintani, Paula S. Norris, Jose-ignacio Rodriguez-barbosaAbstract:The cosignaling network mediated by the Herpesvirus Entry Mediator (HVEM; TNFRSF14) functions as a dual directional system that involves proinflammatory ligand, lymphotoxin that exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT; TNFSF14), and the inhibitory Ig family member B and T lymphocyte attenuator (BTLA). To dissect the differential contributions of HVEM/BTLA and HVEM/LIGHT interactions, topographically-specific, competitive, and nonblocking anti-HVEM Abs that inhibit BTLA binding, but not LIGHT, were developed. We demonstrate that a BTLA-specific competitor attenuated the course of acute graft-versus-host reaction in a murine F1 transfer semiallogeneic model. Selective HVEM/BTLA blockade did not inhibit donor T cell infiltration into graft-versus-host reaction target organs, but decreased the functional activity of the alloreactive T cells. These results highlight the critical role of HVEM/BTLA pathway in the control of the allogeneic immune response and identify a new therapeutic target for transplantation and autoimmune diseases.
Richard Longnecker - One of the best experts on this subject based on the ideXlab platform.
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Herpesvirus Entry Mediator binding partners mediate immunopathogenesis of ocular herpes simplex virus 1 infection
Mbio, 2020Co-Authors: Seo J Park, Sarah J. Kopp, Rachel E Riccio, Igal Ifergan, Stephen D Miller, Richard LongneckerAbstract:Ocular herpes simplex virus 1 (HSV-1) infection leads to an immunopathogenic disease called herpes stromal keratitis (HSK), in which CD4+ T cell-driven inflammation contributes to irreversible damage to the cornea. Herpesvirus Entry Mediator (HVEM) is an immune modulator that activates stimulatory and inhibitory cosignals by interacting with its binding partners, LIGHT (TNFSF14), BTLA (B and T lymphocyte attenuator), and CD160. We have previously shown that HVEM exacerbates HSK pathogenesis, but the involvement of its binding partners and its connection to the pathogenic T cell response have not been elucidated. In this study, we investigated the role of HVEM and its binding partners in mediating the T cell response using a murine model of ocular HSV-1 infection. By infecting mice lacking the binding partners, we demonstrated that multiple HVEM binding partners were required for HSK pathogenesis. Surprisingly, while LIGHT-/-, BTLA-/-, and CD160-/- mice did not show differences in disease compared to wild-type mice, BTLA-/- LIGHT-/- and CD160-/- LIGHT-/- double knockout mice showed attenuated disease characterized by decreased clinical symptoms, increased retention of corneal sensitivity, and decreased infiltrating leukocytes in the cornea. We determined that the attenuation of disease in HVEM-/-, BTLA-/- LIGHT-/-, and CD160-/- LIGHT-/- mice correlated with a decrease in gamma interferon (IFN-γ)-producing CD4+ T cells. Together, these results suggest that HVEM cosignaling through multiple binding partners induces a pathogenic Th1 response to promote HSK. This report provides new insight into the mechanism of HVEM in HSK pathogenesis and highlights the complexity of HVEM signaling in modulating the immune response following ocular HSV-1 infection.IMPORTANCE Herpes simplex virus 1 (HSV-1), a ubiquitous human pathogen, is capable of causing a progressive inflammatory ocular disease called herpes stromal keratitis (HSK). HSV-1 ocular infection leads to persistent inflammation in the cornea resulting in outcomes ranging from significant visual impairment to complete blindness. Our previous work showed that Herpesvirus Entry Mediator (HVEM) promotes the symptoms of HSK independently of viral Entry and that HVEM expression on CD45+ cells correlates with increased infiltration of leukocytes into the cornea during the chronic inflammatory phase of the disease. Here, we elucidated the role of HVEM in the pathogenic Th1 response following ocular HSV-1 infection and the contribution of HVEM binding partners in HSK pathogenesis. Investigating the molecular mechanisms of HVEM in promoting corneal inflammation following HSV-1 infection improves our understanding of potential therapeutic targets for HSK.
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characterization of sex differences in ocular herpes simplex virus 1 infection and herpes stromal keratitis pathogenesis of wild type and Herpesvirus Entry Mediator knockout mice
mSphere, 2019Co-Authors: Rachel E Riccio, Richard Longnecker, Seo J Park, Sarah J. KoppAbstract:Sex differences related to immune response and inflammation play a role in the susceptibility and pathogenesis of a variety of viral infections and disease (S. L. Klein, Bioessays 34:1050-1059, 2012, https://doi.org/10.1002/bies.201200099). Herpes simplex virus 1 (HSV-1) causes chronic inflammatory disease in the cornea, an immune-privileged tissue, resulting in irreversible damage and blindness in affected individuals (A. Rowe, A. St Leger, S. Jeon, D. K. Dhaliwal, et al., Prog Retin Eye Res 32:88-101, 2013, https://doi.org/10.1016/j.preteyeres.2012.08.002). Our research focuses on the role of Herpesvirus Entry Mediator (HVEM) as an immune regulator during ocular HSV-1 infection. Mice lacking HVEM (HVEM knockout [KO] mice) exhibit lower levels of immune cell infiltrates and less severe ocular disease in the cornea than wild-type (WT) mice. As sex differences contribute to pathogenesis in many inflammatory diseases, we tested whether sex acts as a biological variable in the immune response to HSV-1 infection and herpes stromal keratitis (HSK) pathogenesis. Adult male and female WT and HVEM KO mice were inoculated with HSV-1 via corneal scarification and monitored daily for disease course. Viral titers were determined, and immune cell infiltrates were collected and analyzed. Our results indicated no significant differences in viral titers in tear film or affected tissues, in immune cell infiltration, or in clinical symptoms between males and females of either genotype. These results suggest that sex is not a significant biological variable in this experimental model and that male and female mice of the C57BL/6 background can be used similarly in studies of ocular HSV-1 pathogenesis.IMPORTANCE Sex hormones have come to be considered an important factor for the development of certain diseases only recently and as such should continue to be considered a biological variable. Ocular HSV-1, and the resulting HSK, is the leading cause of infectious blindness worldwide. We compared levels of ocular HSV-1 infection and pathogenesis in the two sexes and found no significance differences between male and female WT mice or HVEM KO mice.
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characterization of sex differences in ocular hsv 1 infection and herpes stromal keratitis pathogenesis of wild type and Herpesvirus Entry Mediator knockout mice
bioRxiv, 2019Co-Authors: Rachel E Riccio, Richard Longnecker, Seo J Park, Sarah J. KoppAbstract:ABSTRACT Sex differences related to immune response and inflammation play a role in the susceptibility and pathogenesis of a variety of viral infections and disease (S. L. Klein, Bioessays 34:1050-9, 2012). Herpes simplex virus type 1 (HSV-1) causes chronic inflammatory disease in the cornea, an immune privileged tissue, resulting in irreversible damage and blindness in affected individuals (A. Rowe, A. St Leger, S. Jeon, D. K. Dhaliwal, J. E. Knickelbein, and E. Vilain, Prog Retin Eye Res 32:88-101, 2013). Our research focuses on the role of Herpes Viral Entry Mediator (HVEM) as an immune regulator during ocular HSV-1 infection. Mice lacking HVEM (HVEM KO) exhibit lower immune cell infiltrates and less severe ocular disease in the cornea compared to wild type (WT) mice. As sex differences contribute to pathogenesis in many inflammatory diseases, we tested sex as a biological variable in the immune response to HSV-1 infection and Herpes Stromal Keratitis pathogenesis (HSK). Adult male and female WT and HVEM KO mice were inoculated with HSV-1 via corneal scarification and monitored daily for disease course. Viral titers and immune cell infiltrates were collected and analyzed. Our results indicate no significant difference in viral titers in tear film or affected tissues; immune cell infiltration; or clinical symptoms between males and females of either genotype. These results suggest that sex is not a significant biological variable in this experimental model, and that male and female mice can similarly be used in studies of ocular HSV-1 pathogenesis. IMPORTANCE Sex hormones have only recently been considered as an important factor for the development of certain diseases and as such should continue to be considered as a biological variable. Ocular Herpesvirus Type 1 (HSV-1), and the resulting Herpes Stromal Keratitis, is the leading cause of infectious blindness worldwide. We compared ocular HSV-1 infection and pathogenesis between sexes and found no significance difference between male and female wild type mice or Herpesvirus Entry Mediator knockout mice. Therefore, male and female mice can be used interchangeably in studying ocular HSV-1 pathogenesis.
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Characterization of Sex Differences in Ocular Herpes Simplex Virus 1 Infection and Herpes Stromal Keratitis Pathogenesis of Wild-Type and Herpesvirus Entry Mediator Knockout Mice
American Society for Microbiology, 2019Co-Authors: Rachel E Riccio, Richard Longnecker, Seo J Park, Sarah J. KoppAbstract:Sex hormones have come to be considered an important factor for the development of certain diseases only recently and as such should continue to be considered a biological variable. Ocular HSV-1, and the resulting HSK, is the leading cause of infectious blindness worldwide. We compared levels of ocular HSV-1 infection and pathogenesis in the two sexes and found no significance differences between male and female WT mice or HVEM KO mice.Sex differences related to immune response and inflammation play a role in the susceptibility and pathogenesis of a variety of viral infections and disease (S. L. Klein, Bioessays 34:1050–1059, 2012, https://doi.org/10.1002/bies.201200099). Herpes simplex virus 1 (HSV-1) causes chronic inflammatory disease in the cornea, an immune-privileged tissue, resulting in irreversible damage and blindness in affected individuals (A. Rowe, A. St Leger, S. Jeon, D. K. Dhaliwal, et al., Prog Retin Eye Res 32:88–101, 2013, https://doi.org/10.1016/j.preteyeres.2012.08.002). Our research focuses on the role of Herpesvirus Entry Mediator (HVEM) as an immune regulator during ocular HSV-1 infection. Mice lacking HVEM (HVEM knockout [KO] mice) exhibit lower levels of immune cell infiltrates and less severe ocular disease in the cornea than wild-type (WT) mice. As sex differences contribute to pathogenesis in many inflammatory diseases, we tested whether sex acts as a biological variable in the immune response to HSV-1 infection and herpes stromal keratitis (HSK) pathogenesis. Adult male and female WT and HVEM KO mice were inoculated with HSV-1 via corneal scarification and monitored daily for disease course. Viral titers were determined, and immune cell infiltrates were collected and analyzed. Our results indicated no significant differences in viral titers in tear film or affected tissues, in immune cell infiltration, or in clinical symptoms between males and females of either genotype. These results suggest that sex is not a significant biological variable in this experimental model and that male and female mice of the C57BL/6 background can be used similarly in studies of ocular HSV-1 pathogenesis
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Herpesvirus Entry Mediator and ocular Herpesvirus infection more than meets the eye
Journal of Virology, 2017Co-Authors: Rebecca G Edwards, Richard LongneckerAbstract:As its name suggests, the host receptor Herpesvirus Entry Mediator (HVEM) facilitates herpes simplex virus (HSV) Entry through interactions with a viral envelope glycoprotein. HVEM also bridges several signaling networks, binding ligands from both tumor necrosis factor (TNF) and immunoglobulin (Ig) superfamilies with diverse, and often opposing, outcomes. While HVEM was first identified as a viral Entry receptor for HSV, it is only recently that HVEM has emerged as an important host factor in immunopathogenesis of ocular HSV type 1 (HSV-1) infection. Surprisingly, HVEM exacerbates disease development in the eye independently of Entry. HVEM signaling has been shown to play a variety of roles in modulating immune responses to HSV and other pathogens, and there is increasing evidence that these effects are responsible for HVEM-mediated pathogenesis in the eye. Here, we review the dual branches of HVEM function during HSV infection: Entry and immunomodulation. HVEM is broadly expressed; intersects two important immunologic signaling networks; and impacts autoimmunity, infection, and inflammation. We hope that by understanding the complex range of effects mediated by this receptor, we can offer insights applicable to a wide variety of disease states.
Gary H Cohen - One of the best experts on this subject based on the ideXlab platform.
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herpes simplex virus glycoprotein d interferes with binding of Herpesvirus Entry Mediator to its ligands through downregulation and direct competition
Journal of Virology, 2010Co-Authors: Katie M Stiles, Roselyn J Eisenberg, Gary H Cohen, Charles J Whitbeck, Huan Lou, Claude KrummenacherAbstract:To initiate membrane fusion and virus Entry, herpes simplex virus (HSV) gD binds to a cellular receptor such as Herpesvirus Entry Mediator (HVEM). HVEM is a tumor necrosis factor (TNF) receptor family member with four natural ligands that either stimulate (LIGHT and LTα) or inhibit (BTLA and CD160) T cell function. We hypothesized that the interaction of gD with HVEM affects the binding of natural ligands, thereby modulating the immune response during infection. Here, we investigated the effect that gD has on the interaction of HVEM with its natural ligands. First, HSV gD on virions or cells downregulates HVEM from the cell surface. Similarly, trans-interaction with BTLA or LIGHT also downregulates HVEM from the cell surface, suggesting that HSV may subvert a natural mechanism for regulating HVEM activity. Second, we showed that wild-type gD had the lowest affinity for HVEM compared with the four natural ligands. Moreover, gD directly competed for binding to HVEM with BTLA but not LTα or LIGHT, indicating the possibility that gD selectively controls HVEM signals. On the other hand, natural ligands influence the use of HVEM by HSV. For instance, soluble BTLA, LTα, and LIGHT inhibited the binding of wild-type gD to HVEM, and soluble BTLA and LTα blocked HSV infection of HVEM-expressing cells. Thus, gD is at the center of the interplay between HVEM and its ligands. It can interfere with HVEM function in two ways, by competing with the natural ligands and by downregulating HVEM from the cell surface.
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Targeting of antigen to the Herpesvirus Entry Mediator augments primary adaptive immune responses.
Nature medicine, 2008Co-Authors: Marcio O. Lasaro, Roselyn J Eisenberg, Gary H Cohen, J. Charles Whitbeck, Nia Tatsis, Scott E. Hensley, Shih-wen Lin, John J. Rux, E. John Wherry, Hildegund C.j. ErtlAbstract:Interactions between the Herpesvirus Entry Mediator (HVEM) and the B- and T-lymphocyte attenuator (BTLA) inhibit B and T cell activation. HVEM-BTLA interactions are blocked by herpes simplex virus (HSV) glycoprotein D (gD) through binding of its N-terminal domain to the BTLA binding site of HVEM. In this study, we inserted viral antigens into the C-terminal domain of gD and expressed these antigens with plasmid or E1-deleted (replication-defective) adenovirus vectors. Viral antigens fused to gD induced T and B cell responses to the antigen that were far more potent than those elicited by the same antigen expressed without gD. The immunopotentiating effect required binding of the gD chimeric protein to HVEM. Overall, the studies demonstrate that targeting of antigen to the BTLA binding site of HVEM augments the immunogenicity of vaccines.
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Nectin-1/HveC Mediates herpes simplex virus type 1 Entry into primary human sensory neurons and fibroblasts.
Journal of neurovirology, 2005Co-Authors: Scott A. Simpson, Claude Krummenacher, Gary H Cohen, Michael D. Manchak, Elizabeth Hager, J. Charles Whitbeck, Myron J. Levin, Curt R. Freed, Christine L. Wilcox, Roselyn J EisenbergAbstract:Immunocytochemistry detects nectin-1/HveC, nectin-2/HveB, and HVEM/HveA on the surface of sensory neurons and fibroblasts grown as primary cultures from human dorsal root ganglia. Viral Entry into these cultured cells was assayed by infection with a recombinant herpes simplex virus type 1 (HSV-1) expressing green fluorescent protein. Soluble, truncated nectin-1 polypeptide, as well as polyclonal and monoclonal antibodies against nectin-1, inhibited infection of neurons, whereas polypeptides and antibodies capable of inhibiting HSV-1 interaction with nectin-2 and Herpesvirus Entry Mediator (HVEM) failed to prevent infection of neuronal cells. These results demonstrate that nectin-1 is the primary receptor for HSV-1 Entry into human fetal neurons. Viral Entry into fibroblasts was also reduced by soluble nectin-1 but not by soluble HVEM. However, in contrast to the results obtained with neurons, antibodies against receptors failed to inhibit Entry into fibroblasts, indicating that unlike neurons, fibroblasts have multiple receptors or mechanisms for HSV-1 Entry.
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Comparative usage of Herpesvirus Entry Mediator A and nectin-1 by laboratory strains and clinical isolates of herpes simplex virus.
Virology, 2004Co-Authors: Claude Krummenacher, Gary H Cohen, Isabelle Baribaud, J. Charles Whitbeck, Frédéric Baribaud, Manuel Ponce De Leon, Roselyn J EisenbergAbstract:The Herpesvirus Entry Mediator A (HVEM/HveA) and nectin-1 (HveC/CD111) are two major receptors for herpes simplex virus (HSV). Although structurally unrelated, both receptors can independently mediate Entry of wild-type (wt) HSV-1 and HSV-2 by interacting with the viral envelope glycoprotein D (gD). Laboratory strains with defined mutations in gD (e.g. rid1) do not use HVEM but use nectin-2 (HveB/CD112) for Entry. The relative usage of HVEM and nectin-1 during HSV infection in vivo is not known. In the absence of a defined in vivo model, we used in vitro approaches to address this question. First, we screened HSV clinical isolates from various origins for receptor tropism and found that all used both HVEM and nectin-1. Second, we determined the numbers of surface receptors on various susceptible and resistant cell lines as well as on primary fibroblasts derived from an individual with cleft lip/palate ectodermal dysplasia (CLPED1). Although CLPED1 cells can only express a defective form of nectin-1, they allowed Entry of wild type and mutant HSV strains by usage of either HVEM or nectin-2. Finally, we compared the ability of HVEM and nectin-1 to mediate Entry when expressed at varying cell surface densities. Both receptors showed a direct relationship between the number of receptors and HSV susceptibility. Direct comparison of receptors suggests that nectin-1 is more efficient at promoting Entry than HVEM. Overall, our data suggest that both receptors play a role during HSV infection in vivo and that both are highly efficient even at low levels of expression.
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porcine hvec a member of the highly conserved hvec nectin 1 family is a functional alphaHerpesvirus receptor
Virology, 2001Co-Authors: Richard S B Milne, Claude Krummenacher, Roselyn J Eisenberg, Sarah A Connolly, Gary H CohenAbstract:Human Herpesvirus Entry Mediator C (HveC) is an alphaHerpesvirus receptor which binds to virion glycoprotein D (gD). We identified porcine HveC and studied its interaction with pseudorabies virus (PrV) and herpes simplex virus type 1 (HSV-1) gD. Porcine and human HveC have 96% amino acid identity and HveC from African green monkey, mouse, hamster, and cow are similarly conserved. Porcine HveC mediates Entry of HSV-1, HSV-2, PrV, and bovine Herpesvirus type 1. Truncated soluble forms of HSV-1 and PrV gD bind competitively to porcine HveC. Biosensor analysis shows that PrV gD binds with a 10-fold higher affinity than HSV-1 gD. Monoclonal antibodies against human HveC recognize the porcine homologue and can block gD binding and Entry of HSV-1 and PrV. Porcine HveC is functionally indistinguishable from human HveC. Our results are consistent with the suggestion that HveC is a pan-alphaHerpesvirus receptor that interacts with a conserved structural domain of gD.
Homayon Ghiasi - One of the best experts on this subject based on the ideXlab platform.
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The Absence of Lymphotoxin-α, a Herpesvirus Entry Mediator (HVEM) Ligand, Affects Herpes Simplex Virus 1 Infection In Vivo Differently than the Absence of Other HVEM Cellular Ligands.
Journal of virology, 2019Co-Authors: Shaohui Wang, Satoshi Hirose, Homayon GhiasiAbstract:Previously, we reported that the absence of Herpesvirus Entry Mediator (HVEM) decreases latency but not primary infection in ocularly infected mice. Recently, we reported that similar to the absence of HVEM, the absence of HVEM ligands (i.e., LIGHT, CD160, and B and T lymphocyte attenuator [BTLA]) also decreased latency but not primary infection. Similar to LIGHT, CD160, and BTLA, another member of tumor necrosis factor (TNF) superfamily, lymphotoxin-α (LTα), also interacts with HVEM. To determine whether LTα decreases latency in infected mice, we ocularly infected LTα-/- mice with latency-associated transcript-positive [LAT(+)] and LAT(-) viruses using similarly infected wild-type (WT) mice as controls. In contrast to WT C57BL/6 mice, LTα-/- mice were highly susceptible to ocular herpes simplex virus 1 (HSV-1) infection, independent of the presence or absence of LAT. Survival was partially restored by adoptive transfer of CD4+, CD8+, or total T cells. Infected LTα-/- mice had significantly higher corneal scarring than WT mice, and adoptive T cell transfer did not alter the severity of eye disease. In contrast to results in WT mice, the amount of latency was not affected by the absence of LAT. The amount of LAT RNA in LTα-/- mice infected with LAT(+) virus was similar to that in WT mice, and adoptive T cell transfer did not alter LAT RNA levels in LTα-/- infected mice. Increased latency in the absence of LTα correlated with upregulation of HVEM, LIGHT, CD160, and BTLA transcripts as well as with an increase in markers of T cell exhaustion. The results of our study suggest that LTα has antipathogenic and anti-inflammatory functions and may act to protect the host from infection.IMPORTANCE Recently, we evaluated the effects of HVEM and its ligands (LIGHT, CD160, and BTLA) on HSV-1 infectivity. However, the effect of LTα, another member of the TNF superfamily, on HSV-1 latency and eye disease is not known. Here, we demonstrate increased latency and corneal scarring in LTα-/- infected mice, independent of the presence of LAT. In addition, infected mice were highly susceptible to HSV-1 infection, and survival was partially but not significantly restored by adoptive T cell transfer. These results suggest that the absence of LTα affects HSV-1 infectivity differently than the absence of HVEM, LIGHT, CD160, and BTLA.
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Herpes Simplex Virus 1 Latency and the Kinetics of Reactivation Are Regulated by a Complex Network of Interactions between the Herpesvirus Entry Mediator, Its Ligands (gD, BTLA, LIGHT, and CD160), and the Latency-Associated Transcript.
Journal of virology, 2018Co-Authors: Shaohui Wang, Klaus Pfeffer, Mitchell Kronenberg, Alexander V. Ljubimov, Ling Jin, Homayon GhiasiAbstract:Recently, we reported that the Herpesvirus Entry Mediator (HVEM; also called TNFRSF14 or CD270) is upregulated by the latency-associated transcript (LAT) of herpes simplex virus 1 (HSV-1) and that the absence of HVEM affects latency reactivation but not primary infection in ocularly infected mice. gD has been shown to bind to HVEM. LIGHT (TNFSF14), CD160, and BTLA (B- and T-lymphocyte attenuator) also interact with HVEM and can interfere with HSV gD binding. It was not known if LIGHT, CD160, or BTLA affected the level of latency reactivation in the trigeminal ganglia (TG) of latently infected mice. To address this issue, we ocularly infected LIGHT−/−, CD160−/−, and BTLA−/− mice with LAT(+) and LAT(−) viruses, using similarly infected wild-type (WT) and HVEM−/− mice as controls. The amount of latency, as determined by the levels of gB DNA in the TG of the LIGHT−/−, CD160−/−, and BTLA−/− mice infected with either LAT(+) or LAT(−) viruses, was lower than that in WT mice infected with LAT(+) virus and was similar in WT mice infected with LAT(−) virus. The levels of LAT RNA in HVEM−/−, LIGHT−/−, CD160−/−, and BTLA−/− mice infected with LAT(+) virus were similar and were lower than the levels of LAT RNA in WT mice. However, LIGHT−/−, CD160−/−, and BTLA−/− mice, independent of the presence of LAT, had levels of reactivation similar to those of WT mice infected with LAT(+) virus. Faster reactivation correlated with the upregulation of HVEM transcript. The LIGHT−/−, CD160−/−, and BTLA−/− mice had higher levels of HVEM expression, and this, along with the absence of BTLA, LIGHT, or CD160, may contribute to faster reactivation, while the absence of each molecule, independent of LAT, may have contributed to lower latency. This study suggests that, in the absence of competition with gD for binding to HVEM, LAT RNA is important for WT levels of latency but not for WT levels of reactivation. IMPORTANCE The effects of BTLA, LIGHT, and CD160 on latency reactivation are not known. We show here that in BTLA, LIGHT, or CD160 null mice, latency is reduced; however, HVEM expression is upregulated compared to that of WT mice, and this upregulation is associated with higher reactivation that is independent of LAT but dependent on gD expression. Thus, one of the mechanisms by which BTLA, LIGHT, and CD160 null mice enhance reactivation appears to be the increased expression of HVEM in the presence of gD. Thus, our results suggest that blockade of HVEM-LIGHT-BTLA-CD160 contributes to reduced HSV-1 latency and reactivation.
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Interactions between Herpesvirus Entry Mediator (TNFRSF14) and Latency-Associated Transcript during Herpes Simplex Virus 1 Latency
Journal of virology, 2013Co-Authors: Sariah J. Allen, Carl F. Ware, Antje Rhode-kurnow, Kevin R. Mott, Xianzhi Jiang, Dale Carpenter, J. Ignacio Rodriguez-barbosa, Clinton Jones, Steven L. Wechsler, Homayon GhiasiAbstract:Herpesvirus Entry Mediator (HVEM) is one of several cell surface proteins herpes simplex virus (HSV) uses for attachment/Entry. HVEM regulates cellular immune responses and can also increase cell survival. Interestingly, latency-associated transcript (LAT), the only viral gene consistently expressed during neuronal latency, enhances latency and reactivation by promoting cell survival and by helping the virus evade the host immune response. However, the mechanisms of these LAT activities are not well understood. We show here for the first time that one mechanism by which LAT enhances latency and reactivation appears to be by upregulating HVEM expression. HSV-1 latency/reactivation was significantly reduced in Hvem−/− mice, indicating that HVEM plays a significant role in HSV-1 latency/reactivation. Furthermore, LAT upregulated HVEM expression during latency in vivo and also when expressed in vitro in the absence of other viral factors. This study suggests a mechanism whereby LAT upregulates HVEM expression potentially through binding of two LAT small noncoding RNAs to the HVEM promoter and that the increased HVEM then leads to downregulation of immune responses in the latent microenvironment and increased survival of latently infected cells. Thus, one of the mechanisms by which LAT enhances latency/reactivation appears to be through increasing expression of HVEM.