LIGHT, a New Member of the TNF Superfamily, and Lymphotoxin α Are Ligands for Herpesvirus Entry Mediator

TLDR

Herpes simplex virus enters activated T lymphocytes by envelope glycoprotein D binding to the orphan TNF receptor HVEM, while the 29‑kDa transmembrane protein LIGHT from activated T cells also engages HVEM but does not complex with LTα or LTβ. We show that HVEM binds secreted lymphotoxin α and LIGHT, and that HSV‑1 gD blocks LIGHT binding and interferes with HVEM‑mediated viral entry, thereby defining gD as a membrane‑bound viokine and positioning LIGHT‑HVEM as key elements of the lymphotoxin cytokine‑receptor system.

Abstract

Herpes simplex virus (HSV) 1 and 2 infect activated T lymphocytes by attachment of the HSV envelope glycoprotein D (gD) to the cellular herpesvirus entry mediator (HVEM), an orphan member of the tumor necrosis factor receptor superfamily. Here, we demonstrate that HVEM binds two cellular ligands, secreted lymphotoxin α (LTα) and LIGHT, a new member of the TNF superfamily. LIGHT is a 29 kDa type II transmembrane protein produced by activated T cells that also engages the receptor for the LTαβ heterotrimer but does not form complexes with either LTα or LTβ. HSV1 gD inhibits the interaction of HVEM with LIGHT, and LIGHT and gD interfere with HVEM-dependent cell entry by HSV1. This characterizes herpesvirus gD as a membrane-bound viokine and establishes LIGHT-HVEM as integral components of the lymphotoxin cytokine-receptor system.8 These authors made equal contributions.