HVEM

Official Full Name

TNF receptor superfamily member 14

Organism

Homo sapiens

GeneID

8764

Background

This gene encodes a member of the TNF (tumor necrosis factor) receptor superfamily. The encoded protein functions in signal transduction pathways that activate inflammatory and inhibitory T-cell immune response. It binds herpes simplex virus (HSV) viral envelope glycoprotein D (gD), mediating its entry into cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

Synonyms

TNFRSF14; TR2; ATAR; HVEA; HVEM; CD270; LIGHTR;

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Detailed Information

Recent Research Progress

HVEM, the host receptor herpesvirus entry mediator, also known as TNFRSR14, as its name suggests, facilitates herpes simplex virus (HSV) entry through interactions with a viral envelope glycoprotein. As shown in the diagram below, HVEM also bridges several signaling networks, combining ligands from the 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 the immunogenic pathogenesis of HSV-1 infection in the eye. Surprisingly, HVEM exacerbates the development of the disease, regardless of entry. HVEM signaling plays a multiple role in regulating immune responses to HSV and other pathogens, and there is increasing evidence that these effects are responsible for HVEM-mediated eye pathogenesis. There are dual branches of HVEM function during HSV infection: entry and immunomodulation. HVEM is broadly expressed, intersecting two important immune signaling networks and affecting autoimmunity, infection, and inflammation.

HVEM Figure 1. Schematic depicting the facilitation of bidirectional signaling of HVEM (Edwards R G, et al. 2017).

According to recent researches, HVEM, as a ligand of BTLA (B- and T-lymphocyte attenuator, also known as CD272), has emerged as a major and complex co-signaling molecule, identified as a new target to enhance anti-tumor immunity. HVEM provides a stimulation signal upon binding to TNF member LIGHT (TNFSF14) on T cells and B cells. And, HVEM can also provide suppression signals to T cells when bound to BTLA. Thus, HVEM may be viewed as a molecular switch in T cells. Despite the complexity of ligand binding, the inhibitory function of HVEM seems to be dominant. These studies further supported that the BTLA/HVEM interaction also act as an inhibitors and might be a targetable interaction. Moreover, HVEM targeting could be attractive if we imagine a joint blockade of the BTLA/HVEM inhibitory pathway and triggering of the LIGHT/HVEM co-stimulatory pathway.

Additionally, the HVEM network could be new directions in targeting novel co-stimulatory/co-inhibitory molecules for cancer therapy. The potential roles of HVEM and its ligands in tumor progression and immune response escape has been confirmed. Blockade or enhancement of these pathways may help improving cancer therapy.

Coincidentally, Tsang J Y S, et al. indicated HVEM played significant oncogenic role in breast carcinogenesis, and may also be a tumor-specific target. HVEM expression in breast cancers was associated with aggressive tumor features. It is possible that HVEM acts directly on breast cancer cells in promoting cell cycle progression, and indirectly by inhibiting the tumor immune environment. Thus, HVEM may be a synergistic target for the immunotherapy of breast cancers. What’s more, HVEM is highly expressed in ovarian serous adenocarcinoma tissues and is correlated with the patient clinicopathological features. Therefore, HVEM may provide a basis in the search for a new targeting treatment for ovarian serous adenocarcinoma.

References:

Edwards R G, et al. Herpes virus entry mediator (HVEM) and ocular herpes infection: more than meets the eye. Journal of Virology, 2017, 91(13).
Spodzieja M, et al. Design of short peptides to block BTLA/HVEM interactions for promoting anticancer T-cell responses. Plos One, 2017, 12(6):e0179201.
Tsang J Y S, et al. Expression and Clinical Significance of Herpes Virus Entry Mediator (HVEM) in Breast Cancer. Annals of Surgical Oncology, 2017, 24(2):1-9.
Fang Y, et al. High expression of herpesvirus entry mediator (HVEM) in ovarian serous adenocarcinoma tissue. Journal of B.u.on. Official Journal of the Balkan Union of Oncology, 2017, 22(1):80.

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