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  • Review Article
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Cross-regulation between herpesviruses and the TNF superfamily members

Nature Reviews Immunology volume 8, pages 861–873 (2008)Cite this article

Key Points

  • The attachment of herpesviruses to host cells requires many steps, including initial non-specific attachment, specific attachment to entry receptors and viral fusion with the cell membrane.

  • Herpes simplex virus (HSV) enters cells using the gD-binding receptors herpesvirus entry mediator, nectin-1, nectin-2 and a form of heparan sulphate, as well as the gB-binding receptor paired immunoglobulin-like type 2 receptor-α. HSV can use signalling that is induced by these receptors to regulate host immune responses.

  • The human herpesviruses express several homologues of tumour-necrosis factor (TNF) receptors, which they use to provide survival and, in some cases, transforming signals to the host cells.

  • An important mechanism of viral clearance that is used by the host immune system involves the use of the death-domain-containing TNF receptors CD95 and TNF-related apoptosis-inducing ligand receptor (TRAILR) to induce apoptosis of infected cells.

  • Adaptive immune responses are boosted through co-stimulatory signals from TNF receptors such as OX40, which increase the numbers of virus-specific T cells to limit viral replication.

  • The chronic pathogen cytomegalovirus induces interferon production and lymphotoxin-β receptor activation in infected cells, which results in reduced virus production and the establishment of host–pathogen 'détente'; this allows survival of both the virus and the host cell.

Abstract

Herpesviruses have evolved numerous strategies to subvert host immune responses so they can coexist with their host species. These viruses 'co-opt' host genes for entry into host cells and then express immunomodulatory genes, including mimics of members of the tumour-necrosis factor (TNF) superfamily, that initiate and alter host-cell signalling pathways. TNF superfamily members have crucial roles in controlling herpesvirus infection by mediating the direct killing of infected cells and by enhancing immune responses. Despite these strong immune responses, herpesviruses persist in a latent form, which suggests a dynamic relationship between the host immune system and the virus that results in a balance between host survival and viral control.

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Figure 1: Herpes simplex virus entry receptors and ligands.
Figure 2: Co-stimulatory and inhibitory signalling by HVEM and PILRα.
Figure 3: Tumour-necrosis-factor-receptor-like signalling of viral proteins.
Figure 4: The role of tumour-necrosis factor receptors in the control of viral replication.

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Acknowledgements

We apologize to all our colleagues whose work could not be cited because of space limitations.

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Authors and Affiliations

  1. Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, 92037, California, USA

    John R. Šedý & Carl F. Ware

  2. The Feinberg School of Medicine, Northwestern University, 320 East Superior Street, Chicago, 60611, Illinois, USA

    Patricia G. Spear

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Glossary

Latent phase

A phase of a virus life cycle that is characterized by the absence of most or all viral-gene transcription despite the presence of the viral genome in host cells.

Lytic replicative cycle

A phase of a virus life cycle that is characterized by active viral-gene transcription and viral-particle production and that commonly results in cell death.

Viral glycoprotein

A glycoprotein that is found in the outer envelope of viruses. Of the 12 glycoproteins that are found in the outer envelope of herpesviruses, gB, gH and gL are the most highly conserved and are thought to be important for virus–host-cell membrane fusion.

Heparan sulphate

A ubiquitously expressed glycosaminoglycan found on most proteoglycans. Most herpesviruses target and use heparan sulphate as a receptor for initial attachment to host cells.

Cysteine-rich domain

(CRD). A protein domain that is present in several copies in most tumour-necrosis factor receptors (TNFRs) and that contains up to six cysteine residues, which form up to three disulphide bonds. CRDs are named according to their position in TNFRs and typically CRD2 and CRD3 are required for binding of the receptors to members of the TNF superfamily.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). A short peptide motif (Ile/Val/Leu/Ser-X-Tyr-X-X-Leu/Val; in which X denotes any amino acid) that is present in the cytoplasmic domain of inhibitory receptors. When the tyrosine residue is phosphorylated, ITIMs recruit lipid or tyrosine phosphatases that mediate the inhibitory function of these receptors.

Immunoreceptor tyrosine-based activation motif

A structural motif containing tyrosine residues, which is found in the cytoplasmic tails of several signalling molecules. The motif has the form Tyr-X-X-(Leu/Ile), in which X denotes any amino acid, and the tyrosine is a target for phosphorylation by SRC tyrosine kinases and subsequent binding of proteins containing SRC-homology 2 domains.

Nuclear factor-κB

(NF-κB). A family of transcription factors (including NF-κB1 (also known as p50), NF-κB2 (also known as p52), cREL, RELA and RELB) that is important for pro-inflammatory and anti-apoptotic responses and for the development of lymphoid tissues. Each of these responses is mediated by canonical and non-canonical signalling pathways.

Death receptor

A cell-surface receptor that can mediate cell death following ligand-induced trimerization. The best-studied members of the death-receptor family include tumour-necrosis factor (TNF) receptor 1, CD95 and two receptors for TNF-related apoptosis-inducing ligand (TRAILR1 and TRAILR2).

Lipid raft

A cholesterol- and glycosphingolipid-rich region of the plasma membrane that provides ordered structure to the lipid bilayer and can include or exclude specific signalling molecules and complexes.

Activator protein 1

A transcription factor complex composed of a heterodimer of JUN and FOS subunits that is necessary for the induction of interleukin-2 transcription in T cells. JUN and FOS subunits are members of a family of leucine-zipper-containing proteins that are induced following activation of extracellular-signal-regulated kinase and JUN N-terminal kinase.

Mitogen-activated protein kinase

A family of serine/threonine kinases that are activated by various mitogenic stimuli and lead to the activation of extracellular-signal-regulated kinase, JUN N-terminal kinase or p38.

Phosphoinositide 3-kinase

(PI3K). A lipid kinase that generates phosphatidylinositol-3,4,5-trisphosphate, which can be bound by pleckstrin-homology-domain-containing proteins, such as protein kinase B. PI3K activation is often associated with survival signals and the activity of anti-apoptotic proteins.

SRC family kinases

A group of structurally related cytoplasmic and membrane-associated enzymes that is named after its prototypical member, SRC. In haematopoietic cells, SRC kinases are the first protein tyrosine kinases to become activated after stimulation through the immunoreceptor. They phosphorylate ITAMs of the immunoreceptors, thereby providing binding sites for SRC homology 2 (SH2)-domain-containing molecules, such as SYK.

Fratricide

A form of cell killing in which one of a group of similar cells kills another member or members of the group.

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Šedý, J., Spear, P. & Ware, C. Cross-regulation between herpesviruses and the TNF superfamily members. Nat Rev Immunol 8, 861–873 (2008). https://doi.org/10.1038/nri2434

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