Herpesvirus entry mediator type A (HVEM. also known as HveA) is related to the receptors for tumor necrosis factor. HVEM is a single transmembrane glycoprotein with a canonical cysteine-rich extracellular domain that binds to two cellular ligands, LIGHT and lymphotoxin o, which are related to TNF. HVEM shares ligand specificity with the LT-beta receptor and the two receptors for TNF, which also bind LT-alfa. HVEM binds a virus-encoded ligand. the envelope glycoprotein D (gD) of Herpes simp/ex virus (HSV) types 1 and 2, and serves as one of several entry routes used by HSV to infect cells. Envelope gD can sterically inhibit the binding of membrane LIGHT to HVEM. acting as a virokine. potentially disrupting signal transduction. The cytoplasmic tail of HVEM "binds TRAF2 and TRAF5 adapter proteins, which propagate signals leading to the activation of N Fa: В and AP-I transcription factors, which control many genes involved in inflammation and immune responses.
HVEM is prominently expressed on cells in the immune system, particularly T cells and dendritic cells and activation of HVEM can provide a costimulator function for T cells. HVEM targets HSV to activated T cells inducing Fas ligand. which can lead to fratricide of bystander lymphocytes. HSV can also infect dendritic cells and block their maturation. Together. HVEM-mediated entry of HSV may lead to localized immune suppression. LIGHT can interfere with HSV entry, thus potentially acting as a virus deterrent. The UL144 gene in human cytomegalovirus (beta-herpesvirus) is a structural homolog of HVEM. suggesting a long evolutionary history between the TNF super-family and herpesviruses.