A Role for Herpesvirus Entry Mediator as the Receptor for Herpes Simplex Virus 1 Entry into Primary Human Trabecular Meshwork Cells

Abstract

The human eye is an important target for infection with herpes simplex virus 1 (HSV-1). Damage to cells forming the trabeculum of the eye by HSV-1 infection could contribute to the development of glaucoma, a major blinding disease. Primary cultures of human trabecular meshwork cells were used as an in vitro model to demonstrate the ability of HSV-1 to enter into and establish a productive infection of the trabeculum. Blocking of entry by anti-herpesvirus entry mediator (HVEM) antibody implicated HVEM as the major receptor for HSV-1 infection.The trabecular meshwork (TM), a specialized eye tissue, is the major site for regulation of the aqueous humor outflow. Inflammation of cells in the TM (trabeculitis) due to herpes simplex virus 1 (HSV-1) infection during corneal endotheliitis and uveitis leads to elevated intraocular pressure, which is a major risk factor for glaucoma, a major blinding disease (1,19,21,25,32). Recently, immunoreactivity for HSV-1 in the trabeculum of the human eye was demonstrated during corneal endotheliitis (1, 19). HSV-1-induced inflammation of human TM cells impedes aqueous outflow and increases intraocular pressure, as has also been reported with Posner Schlossman syndrome (11, 38). The virus has been detected in aqueous humor (40), tears (14), and ciliary ganglia (2) that innervate the cells of the trabeculum. It is, however, ironic that the ability of the virus to invade and productively infect TM cells remains poorly understood and that several aspects of the virus, including the identity of the mediators of the virus entry into these cells, remain unknown. Since HSV-1 infection of TM cells is a risk factor for glaucoma and uveitis, understanding HSV-1 entry and major entry mediators in TM cells becomes important for designing novel strategies to prevent blindness. Therefore, using primary cultures of human TM cells as a model, the present study was undertaken to determine the susceptibility and the mediator(s) of productive HSV-1 entry into TM cells.HSV entry into cells is a complex process that is initiated by specific interaction of viral envelope glycoproteins and host cell surface receptors (31). The virus uses glycoproteins B and C (gB and gC, respectively) to mediate the initial attachment to cell surface heparan sulfate proteoglycans (12,27). Binding of herpesviruses to heparan sulfate proteoglycans likely precedes a conformational change that brings viral glycoprotein D (gD) to the binding domain of host cell surface gD receptors (7,8,15). Thereafter, a concerted action involving gD, its receptor, three additional HSV glycoproteins (gB, gH, and gL), and possibly an additional gH coreceptor triggers fusion of the viral envelope with the plasma membrane of host cells (22,23,26). To date, three classes of HSV entry receptors have been identified (30, 31). They include herpesvirus entry mediator (HVEM) (20), a member of the tumor necrosis factor receptor family (17); nectin-1 and nectin-2 (3, 5, 10), two members of the immunoglobulin superfamily; and specific sites in heparan su...

Role for 3- O -Sulfated Heparan Sulfate as the Receptor for Herpes Simplex Virus Type 1 Entry into Primary Human Corneal Fibroblasts

“…It appears that differential expression of various HSV-1 receptors may indeed influence the course of HSV-1 infection in human cell types. For instance, HVEM is expressed in lymphoid cells, trabecular meshwork cells, and fibroblasts but only weakly in human brain tissues (37,40,62). On the other hand, nectin-1 is highly expressed in central nervous system, corneal epithelium and endothelium, and neuronal cell lines (8,32,64).…”

“…Herpes simplex virus type 1 (HSV-1) infection is the most common cause of infectious blindness in developed countries (33,34,49,62). Following initial infection of epithelial cells, HSV establishes latency in the sensory nerve ganglia of the host (26,58).…”

“…These include a member of the tumor necrosis factor receptor family (40), two members of the nectin family of receptors (21), and the product of certain 3-O-sulfated (3-OS) sulfotransferases (3-OSTs), 3-OS HS (41,55,(57)(58)(59)(60). Herpesvirus entry mediator (HVEM or TNFRSF14) principally mediates entry of HSV-1 and HSV-2 (40, 66) into human T lymphocytes and trabecular meshwork cells and is expressed in many fetal and adult human tissues, including the lung, liver, kidney, and lymphoid tissues (27,32,37,40,62). Nectin-1 and nectin-2, also known as herpesvirus entry proteins C B, respectively, belong to the immunoglobulin superfamily (7,13,21).…”

Binding of herpes simplex virus glycoprotein D to nectin-1 exploits host cell adhesion

“…Consistent with our structure, earlier work shows that soluble nectin-1 blocks virus entry into HVEM-expressing CHO cells and in turn HVEM impairs the virus entry into nectin-1-expressing cells 44 . Th e tissue expression patterns support the alternate receptor functions as nectin-1 is mainly expressed in epithelial, neuronal, endothelial cells and keratinocytes 45 , but HVEM has a more wide-spectrum of tissue expressions, including T lymphocytes and trabecular meshwork cells, as well as lung, liver, kidney and lymphoid tissues 46,47 . Th erefore, the two receptors are used by HSV-1 as its alternate entry / fusion mediators, depending on the infected tissues.…”

Investigations on molecular mechanisms of epithelial cell stress responses

“…HSV-1 has evolved to use multiple receptors and pathways to facilitate entry into different cell types. This differential use of cell membrane receptors is important, and may help in productively infect a wide range of hosts and cell types [71,72].…”