Key Points
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By reprogramming host cellular signalling networks, herpesvirus-encoded G protein-coupled receptors (GPCRs) may subvert cellular signalling and contribute to viral pathogenesis.
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Constitutively-induced and chemokine-induced signalling of the Kaposi's sarcoma-associated herpesvirus-encoded GPCR ORF74 is causative for the development of Kaposi's sarcoma.
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Constitutive signalling of the human cytomegalovirus-encoded GPCR US28 induces cell transformation and proliferation in in vitro and in vivo model systems.
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US28 is present in glioblastoma tumour samples and might be a hitherto neglected target for therapeutic intervention.
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Given the druggability of GPCRs in general and the emerging roles of viral GPCRs, viral GPCRs are promising targets for the treatment of herpesvirus-associated diseases.
Abstract
Herpesviruses encode membrane-associated G protein-coupled receptors (GPCRs) in their viral genomes that are structurally similar to chemokine receptors. These GPCRs hijack GPCR-mediated cellular signalling networks of the host for survival, replication and pathogenesis. In particular the herpesvirus-encoded chemokine receptors ORF74, BILF1 and US28, which are present at inflammatory sites and tumour cells, provide important virus-specific targets for directed therapies. Given the high druggability of GPCRs in general, these viral GPCRs can be considered promising antiviral drug targets.
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Acknowledgements
The authors' work is supported by the Netherlands Organization for Scientific Research (NWO; Veni, Vidi, ECHO grants) and the Dutch Technology Foundation (STW).
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Glossary
- Latent infections
-
A phase of the viral infection cycle in which viral material (such as the genome, proteins or RNA) is maintained in the infected host cell without stimulation of the production and dissemination of new viral particles.
- Herpesviruses
-
A family of double-stranded DNA viruses that consists of three subfamilies; α-, β- and γ-herpesviridae. Herpesviruses establish lifelong infections in their host and require host cells for their replication.
- Virions
-
Viral particles consisting of DNA or RNA surrounded by a protein shell that are the infective forms of a virus.
- Kaposi's sarcoma
-
A cancer of endothelial-type cells that is characterized by numerous lesions on the skin or on mucosal surfaces and is mainly caused by human herpesvirus 8 (also known as Kaposi's sarcoma-associated herpesvirus).
- Angiogenesis
-
The formation of new blood vessels from pre-existing vessels.
- Antagonist
-
A ligand that binds to a receptor and subsequently prevents the binding of endogenous ligands to that receptor (without activating the receptor).
- Constitutively active
-
Receptor-mediated activity that is apparent without prior binding of a ligand. Constitutive activity can be further modulated by the interaction with ligands.
- Oncomodulatory
-
Stimulation of the process of oncogenic transformation by factors that by themself do not display oncogenic potential but aggravate oncogenesis that is triggered by other factors.
- Primary effusion lymphoma
-
A rare B cell-derived non-Hodgkin's type of lymphoma expressing the CD38 cell-surface marker that gives rise to tumour growth in the body cavities.
- Multicentric Castleman's disease
-
Abnormal growth of cells of the lymph system (in multiple lymph nodes) that may develop into lymphoma. Patients develop large lymph nodes and lose immunocompetence.
- Lytic cycle
-
A phase in the viral infection cycle in which production and dissemination of new viral particles occurs. This phase in the viral life cycle is associated with a distinct gene expression profile.
- Inverse agonists
-
Ligands that bind to a receptor and decrease basal signalling.
- Vascular endothelial growth factor
-
(VEGF). A growth factor that acts through its cognate receptor to stimulate the formation of new blood vessels, which provide tissues and tumours with nutrients and oxygen.
- Neoplasia
-
Abnormal tissue growth that occurs as a consequence of dysregulated cell proliferation.
- Interleukin-6
-
(IL-6). A pro-inflammatory cytokine that acts on the IL-6 receptor, resulting in activation of the JAK–STAT (Janus kinase–signal transducer and activator of transcription) axis and subsequent inflammatory and proliferative cellular responses.
- Bystander cells
-
Non-infected cells that are activated by paracrine factors excreted by virus-infected neighbouring cells.
- Autocrine signalling
-
Cellular signalling that occurs in response to ligands that are secreted into the extracellular environment by the same cell.
- Paracrine signalling
-
Activation of signal transduction pathways that occur in response to ligands secreted into the extracellular environment by neighbouring cells.
- Burkitt's lymphoma
-
A B cell non-Hodgkin's lymphoma that is often associated with latent Epstein–Barr virus infection.
- Apoptosis
-
A process of programmed cell death that facilitates the removal of damaged, infected or otherwise obsolete cells from a tissue.
- Major histocompatibility complex
-
(MHC). A cell-surface receptor system that is used by immune cells for interactions with, and activation of, other components of the immune system. The MHC system is used to discriminate 'self' cells from exogenous cells.
- Xenograft tumour model
-
A mouse model of cancer in which human tumours or other tissues are transplanted into mice.
- Permissive cells
-
Cells in which a virus is able to replicate.
- Atherosclerosis
-
A chronic inflammation of the arteries, characterized by lipid-rich lesions with a necrotic core that is separated from the blood by a layer of smooth muscle cells and matrix proteins.
- Allosteric ligand
-
A ligand that binds to a receptor at a different site than an endogenous ligand to subsequently modulate receptor activity and/or binding of endogenous ligands.
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Vischer, H., Siderius, M., Leurs, R. et al. Herpesvirus-encoded GPCRs: neglected players in inflammatory and proliferative diseases?. Nat Rev Drug Discov 13, 123–139 (2014). https://doi.org/10.1038/nrd4189
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DOI: https://doi.org/10.1038/nrd4189
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