Abstract
Herpes virus entry mediator (HVEM) is one of two principal receptors mediating herpes simplex virus (HSV) entry into murine and human cells. It functions naturally as an immune signaling co-receptor, and may participate in enhancing or repressing immune responses depending on the natural ligand used. To investigate whether engagement of HVEM by HSV affects the in vivo response to HSV infection, we generated recombinants of HSV-2(333) that expressed wild-type gD (HSV-2/gD) or mutant gD able to bind to nectin-1 (the other principal entry receptor) but not HVEM. Replication kinetics and yields of the recombinant strains on Vero cells were indistinguishable from those of wild-type HSV-2(333). After intravaginal inoculation with mutant or wild-type virus, adult female C57BL/6 mice developed vaginal lesions and mortality in similar proportions, and mucosal viral titers were similar or lower for mutant strains at different times. Relative to HSV-2/gD, percentages of HSV-specific CD8+ T-cells were similar or only slightly reduced after infection with the mutant strain HSV-2/gD-Δ7-15, in all tissues up to 9 days after infection. Levels of HSV-specific CD4+ T-cells five days after infection also did not differ after infection with either strain. Levels of the cytokine IL-6 and of the chemokines CXCL9, CXCL10, and CCL4 were significantly lower in vaginal washes one day after infection with HSV-2/gD compared with HSV-2/gD-Δ7-15. We conclude that the interaction of HSV gD with HVEM may alter early innate events in the murine immune response to infection, without significantly affecting acute mortality, morbidity, or initial T-cell responses after lethal challenge.
Highlights
Infection of cells with herpes simplex virus (HSV) requires binding of specific cell surface receptors to viral ligands, with subsequent fusion of the viral envelope with a cell membrane and delivery of viral DNA into the cell [1,2]
It is expressed in many tissues, including cells of the immune system, where its known natural ligands include LIGHT [5], lymphotoxin-a [5], B and T lymphocyte attenuator (BTLA) [6,7], and CD160 [8]
Entry of the HSV-2/gD-Q27P and HSV-2/gD-D7-15 viruses was severely impaired in cells expressing either human or murine herpes virus entry mediator (HVEM)
Summary
Infection of cells with herpes simplex virus (HSV) requires binding of specific cell surface receptors to viral ligands, with subsequent fusion of the viral envelope with a cell membrane and delivery of viral DNA into the cell [1,2]. Several viral proteins are capable of mediating attachment, binding of the gD glycoprotein to one of its receptors is required for subsequent membrane fusion and productive HSV infection. HVEM is a member of the tumor necrosis factor (TNF) receptor superfamily of proteins [4] It is expressed in many tissues, including cells of the immune system, where its known natural ligands include LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes) [5], lymphotoxin-a [5], B and T lymphocyte attenuator (BTLA) [6,7], and CD160 [8]. Recent studies in a systemic model of bacterial infection suggest that the HVEM-BTLA interaction may predominate to inhibit early innate immune responses through effects on proinflammatory cytokine production [13]
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