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Viral hijacking of G-protein-coupled-receptor signalling networks

Key Points

  • Viral genomes have evolved to exploit an extraordinarily diverse repertoire of strategies to ensure their replicative success. It is therefore not surprising that numerous viral genes encode molecules that use the large family of G-protein-coupled receptors (GPCRs) to recognize and infect cells, or to subvert their signalling capacity to evade immunodetection and to facilitate viral replication.

  • Viral tactics that are used to hijack these essential receptors and harness their activated intracellular signalling pathways include: the use of cellular GPCRs as co-receptors for entry into host cells; the expression of virally encoded GPCRs or their ligands (virokines); the modulation of the expression and function of host-cell GPCRs; and the expression of ligand binding/sequestering proteins.

  • Two chemokine GPCRs, CXCR4 and CCR5, are essential for HIV fusion and cell entry. The activation of intracellular signalling pathways by these HIV co-receptors might also be important in post-entry events that contribute to viral replication and disease progression to AIDS.

  • Virokines and chemokine-binding proteins cause havoc in the immune system by sabotaging the normal signalling capacity and specificity of host chemokines and their receptors.

  • Virally-encoded GPCRs might have a direct role in human diseases. Indeed, the GPCR from Kaposi's-sarcoma-associated herpesvirus has recently been implicated in Kaposi's sarcomagenesis, and the human cytomegalovirus-encoded GPCRs have been implicated in atherosclerosis.

  • The discovery of a crucial role for a viral GPCR in Kaposi's sarcomagenesis has enhanced the appreciation of the oncogenic potential of viral and endogenous GPCRs and their ligands in human cancer.

  • A better understanding of how viruses corrupt intracellular signalling pathways to their advantage might yield valuable information about key cellular regulatory mechanisms, as well as assist in the development of new therapeutic approaches for myriad viral and non-viral human diseases.

Abstract

Viruses use a surprising diversity of approaches to hijack G-protein-coupled receptors and harness their activated intracellular signalling pathways. All of these approaches ultimately function to ensure viral replicative success and often contribute to their pathogenesis. Indeed, a single virus might deploy a repertoire of these strategies to regulate key intracellular survival, proliferative and chemotactic pathways. Understanding the contribution of these biochemical routes to viral pathogenesis might facilitate the development of effective target-specific therapeutic strategies against viral diseases.

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Figure 1: Viral pathogen hijacking of intracellular signalling networks is regulated by GPCRs.
Figure 2: Signalling downstream of HIV gp120–CCR5 interactions.
Figure 3: Interaction of CXCR4 with HIV gp120 promotes lymphocyte migration and apoptosis.
Figure 4: HIV binding to CXCR4 in the absence of CD4 co-receptor promotes apoptosis.
Figure 5: Role of KSHV-GPCR signalling pathways in Kaposi's sarcomagenesis.
Figure 6: KSHV-GPCR signalling in lymphomagenesis.

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Acknowledgements

We apologize to our colleagues whose work could not be cited in this review because of space restrictions.

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Correspondence to Silvia Montaner or J. Silvio Gutkind.

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DATABASES

Swiss Prot

AKT/PKB

AP-1

CCL1

CCL2

CCL3

CCL4

CCR1

CCR2

CCR3

CCR4

CCR5

CCR6

CCR7

CCR8

CCR10

CD4

CD25

CD29

CREB

CXCL12

CXCR1

CXCR2

CXCR4

FAK

FAS ligand

GM-CSF

HIF1α

IL-1β

IL-2

IL-4

IL-6

KDR2

p38

PYK2

Rac1

SRC

TNFα

VEGF

FURTHER INFORMATION

AIDS epidemic update 2003

Glossary

CHEMOKINE

A type of chemotactic cytokine that primarily affects haematopoietic cells in acute and inflammatory processes.

MACROPHAGE

Any cell of the mononuclear-phagocyte system that is characterized by its ability to phagocytose foreign particulate and colloidal material.

MEMORY T CELLS

T lymphocytes that have already encountered an antigen. They are rapidly mobilized to deliver a recall response that surpasses a primary response to new antigens in speed, magnitude and efficacy.

DENDRITIC CELLS

Antigen-presenting cells found in T-cell areas of lymphoid tissues, but also as minor cellular components in most tissues. They have a branched or dendritic morphology and are the most potent stimulators of T-cell responses.

BASOPHIL

Polymorphonuclear, phagocytic leukocyte of the myeloid series.

PERTUSSIS TOXIN

A mixture of proteins that is produced by Bordetella pertussis. It inactivates Gi proteins by catalysing ADP ribosylation of the α-subunit.

ACTIVATOR PROTEIN-1

(AP-1). A transcription-factor complex that comprises a dimer of members of the Fos and Jun families of nuclear phosphoproteins.

FOCAL ADHESIONS

Cellular structures that link the extracellular matrix on the outside of the cell, through integrin receptors, to the actin cytoskeleton inside the cell.

CASPASES

A family of cysteine proteases that cleave after asparagine residues. Initiator caspases are typically activated in response to particular stimuli (for example, caspase-8 after death-receptor ligation, caspase-9 after apoptosome activation, caspase-2 after DNA damage), whereas effector caspases (mainly caspases-3, -6 and -7) are particularly important for the ordered dismantling of vital cellular structures.

DRY MOTIF

A highly conserved aspartic-acid–arginine–tyrosine (DRY) motif in the second cytoplasmic loop of G-protein-coupled receptors for chemokines.

EXANTHEM SUBITUM

Viral disease of infants and young children characterized by a sudden onset of high fever which lasts several days and then suddenly subsides, leaving in its wake a fine red rash.

MONONUCLEOSIS

Acute disease caused by infection with the Epstein–Barr virus (EBV, also known as human herpesvirus 4 (HHV4)). It is characterized by fever and swollen lymph nodes, and an increased level of mononuclear leucocytes or monocytes in the blood.

OPIOID RECEPTORS

Seven-transmembrane receptors that are produced at high levels in the nervous system and that are important for modulating pain responses. Many analgesic drugs, including codeine, morphine and heroin, target these receptors.

POXVIRUSES

A group of enveloped, DNA viruses that can cause pox diseases in vertebrates.

COMPLEMENT

Nine interacting serum proteins (C1–C9) — mostly enzymes — that are activated in a coordinated way and participate in bacterial lysis and macrophage chemotaxis.

MAJOR HISTOCOMPATIBILITY COMPLEX

(MHC). A cluster of genes on human chromosome 6 or mouse chromosome 17 that encode MHC molecules. These molecules are the most polymorphic in the genome, and are the ones recognized by T lymphocytes during transplant rejection. They encode a family of cellular antigens that help the immune system to recognize self from non-self.

MONOCYTES

Large leukocytes with a horseshoe-shaped nucleus. They derive from pluripotent stem cells and become phagocytic macrophages when they enter the tissues.

EOSINOPHIL

A type of white blood cell that has a bi-lobed nucleus and large cytoplasmic granules that contain hydrolytic enzymes and stain readily with eosin.

TH2 LYMPHOCYTE

(T-helper-2 cell). A type of T cell that, through the production of IL-4, IL-13 and other cytokines, can help B cells to produce IgE and other antibodies and, through the secretion of IL-5, IL-3 and others, can promote increased numbers of eosinophilic granulocytes (eosinophils), basophils and mast cells.

DEGRANULATION

The process by which perforin-filled granules are released when a cytotoxic T cell or natural killer cell contacts its target (typically a tumour cell).

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Sodhi, A., Montaner, S. & Gutkind, J. Viral hijacking of G-protein-coupled-receptor signalling networks. Nat Rev Mol Cell Biol 5, 998–1012 (2004). https://doi.org/10.1038/nrm1529

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