Key Points
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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.
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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.
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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.
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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.
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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.
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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.
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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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References
Flower, D. R. Modelling G-protein-coupled receptors for drug design. Biochim. Biophys. Acta 1422, 207–234 (1999).
Pierce, K. L., Premont, R. T. & Lefkowitz, R. J. Seven-transmembrane receptors. Nature Rev. Mol. Cell Biol. 3, 639–650 (2002).
Marinissen, M. J. & Gutkind, J. S. G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol. Sci. 22, 368–376 (2001). Focuses on the molecular mechanisms by which GPCRs signal to the nucleus through an intricate network of second-messenger-generating systems and MAPK signalling pathways.
Hamm, H. E. The many faces of G protein signaling. J. Biol. Chem. 273, 669–672 (1998).
Gutkind, J. S. Regulation of mitogen-activated protein kinase signaling networks by G protein-coupled receptors. Sci. STKE 2000, RE1 (2000).
Murphy, P. M. Viral exploitation and subversion of the immune system through chemokine mimicry. Nature Immunol. 2, 116–122 (2001). The author presents a critical review on the mechanisms used by viruses to exploit and subvert the immune system.
Yang, T. Y. et al. Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma. J. Exp. Med. 191, 445–454 (2000). Using a transgenic-mouse approach, the authors provide the first indication of the oncogenic potential of the KSHV GPCR in vivo.
Montaner, S. et al. Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell 3, 23–36 (2003). Uses an endothelial-specific retroviral gene delivery system to provide evidence that the KSHV GPCR is sufficient to induce Kaposi's sarcoma-like lesions in mice, and that this viral GPCR promotes the transformation of cells expressing latent KSHV genes in a paracrine manner.
Guo, H. G. et al. Kaposi's sarcoma-like tumors in a human herpesvirus 8 ORF74 transgenic mouse. J. Virol. 77, 2631–2639 (2003).
Sodhi, A., Montaner, S. & Gutkind, J. S. Does dysregulated expression of a deregulated viral GPCR trigger Kaposi's sarcomagenesis? FASEB J. 18, 422–427 (2004).
Joint United Nations Programme on HIV/AIDS (UNAIDS). AIDS epidemic update 2003. (UNAIDS, Geneva, Switzerland, 2003).
Barre-Sinoussi, F. The early years of HIV research: integrating clinical and basic research. Nature Med. 9, 844–846 (2003).
Maddon, P. J. et al. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell 47, 333–348 (1986).
Clapham, P. R., Blanc, D. & Weiss, R. A. Specific cell surface requirements for the infection of CD4-positive cells by human immunodeficiency virus types 1 and 2 and by Simian immunodeficiency virus. Virology 181, 703–715 (1991).
Alkhatib, G. et al. CC CKR5: a RANTES, MIP-1α, MIP-1β receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272, 1955–1958 (1996).
Deng, H. et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 381, 661–666 (1996).
Dragic, T. et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381, 667–673 (1996).
Choe, H. et al. The β-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85, 1135–1148 (1996).
Feng, Y., Broder, C. C., Kennedy, P. E. & Berger, E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, 872–877 (1996). References 15–19 identify the CXCR4 and CCR5 as co-receptors for T-cell (T)-tropic (or X4) or macrophage (M)-tropic (or R5) strains of HIV-1, respectively.
Berger, E. A., Murphy, P. M. & Farber, J. M. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu. Rev. Immunol. 17, 657–700 (1999). An excellent review on the role of chemokine receptors in HIV-1 pathogenesis.
Schuitemaker, H. et al. Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J. Virol. 66, 1354–1360 (1992).
Liu, R. et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).
Samson, M. et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382, 722–725 (1996). References 22 and 23 provide direct evidence for the relevance of CCR5 chemokine receptor in HIV-1 infection.
Bleul, C. C. et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382, 829–833 (1996).
Oberlin, E. et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382, 833–835 (1996).
Alkhatib, G., Locati, M., Kennedy, P. E., Murphy, P. M. & Berger, E. A. HIV-1 coreceptor activity of CCR5 and its inhibition by chemokines: independence from G protein signaling and importance of coreceptor downmodulation. Virology 234, 340–348 (1997).
Atchison, R. E. et al. Multiple extracellular elements of CCR5 and HIV-1 entry: dissociation from response to chemokines. Science 274, 1924–1926 (1996).
Aramori, I. et al. Molecular mechanism of desensitization of the chemokine receptor CCR-5: receptor signaling and internalization are dissociable from its role as an HIV-1 co-receptor. EMBO J. 16, 4606–4616 (1997).
Kinter, A. et al. CC-chemokines enhance the replication of T-tropic strains of HIV-1 in CD4+ T cells: role of signal transduction. Proc. Natl Acad. Sci. USA 95, 11880–11885 (1998).
Alfano, M., Pushkarsky, T., Poli, G. & Bukrinsky, M. The B-oligomer of pertussis toxin inhibits human immunodeficiency virus type 1 replication at multiple stages. J. Virol. 74, 8767–8770 (2000).
Stantchev, T. S. & Broder, C. C. Human immunodeficiency virus type-1 and chemokines: beyond competition for common cellular receptors. Cytokine Growth Factor Rev. 12, 219–243 (2001).
Popik, W., Hesselgesser, J. E. & Pitha, P. M. Binding of human immunodeficiency virus type 1 to CD4 and CXCR4 receptors differentially regulates expression of inflammatory genes and activates the MEK/ERK signaling pathway. J. Virol. 72, 6406–6413 (1998).
Popik, W. & Pitha, P. M. Early activation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase in response to binding of simian immunodeficiency virus to Jurkat T cells expressing CCR5 receptor. Virology 252, 210–217 (1998).
Cohen, P. S. et al. The critical role of p38 MAP kinase in T cell HIV-1 replication. Mol. Med. 3, 339–346 (1997).
Yang, X. & Gabuzda, D. Regulation of human immunodeficiency virus type 1 infectivity by the ERK mitogen-activated protein kinase signaling pathway. J. Virol. 73, 3460–3466 (1999).
Shapiro, L., Heidenreich, K. A., Meintzer, M. K. & Dinarello, C. A. Role of p38 mitogen-activated protein kinase in HIV type 1 production in vitro. Proc. Natl Acad. Sci. USA 95, 7422–7426 (1998).
Kumar, S. et al. Activation of the HIV-1 long terminal repeat by cytokines and environmental stress requires an active CSBP/p38 MAP kinase. J. Biol. Chem. 271, 30864–30869 (1996).
Vicenzi, E. et al. Envelope-dependent restriction of human immunodeficiency virus type 1 spreading in CD4+ T lymphocytes: R5 but not X4 viruses replicate in the absence of T-cell receptor restimulation. J. Virol. 73, 7515–7523 (1999).
Ganju, R. K. et al. The α-chemokine, stromal cell-derived factor-1α, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. J. Biol. Chem. 273, 23169–23175 (1998).
Lee, C. et al. Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways. J. Leukoc. Biol. 74, 676–682 (2003).
Cicala, C. et al. Induction of phosphorylation and intracellular association of CC chemokine receptor 5 and focal adhesion kinase in primary human CD4+ T cells by macrophage-tropic HIV envelope. J. Immunol. 163, 420–426 (1999).
Alimonti, J. B., Ball, T. B. & Fowke, K. R. Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS. J. Gen. Virol. 84, 1649–1661 (2003).
Arthos, J. et al. The role of the CD4 receptor versus HIV coreceptors in envelope-mediated apoptosis in peripheral blood mononuclear cells. Virology 292, 98–106 (2002).
Hesselgesser, J. et al. Neuronal apoptosis induced by HIV-1 gp120 and the chemokine SDF-1α is mediated by the chemokine receptor CXCR4. Curr. Biol. 8, 595–598 (1998).
Roggero, R. et al. Binding of human immunodeficiency virus type 1 gp120 to CXCR4 induces mitochondrial transmembrane depolarization and cytochrome c-mediated apoptosis independently of Fas signaling. J. Virol. 75, 7637–7650 (2001).
Biard-Piechaczyk, M. et al. Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type 1 envelope glycoprotein (gp120). Virology 268, 329–344 (2000).
Berndt, C., Mopps, B., Angermuller, S., Gierschik, P. & Krammer, P. H. CXCR4 and CD4 mediate a rapid CD95-independent cell death in CD4+ T cells. Proc. Natl Acad. Sci. USA 95, 12556–12561 (1998).
Wu, D., LaRosa, G. J. & Simon, M. I. G protein-coupled signal transduction pathways for interleukin-8. Science 261, 101–103 (1993).
Xu, J. et al. Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils. Cell 114, 201–214 (2003).
Sotsios, Y., Whittaker, G. C., Westwick, J. & Ward, S. G. The CXC chemokine stromal cell-derived factor activates a Gi-coupled phosphoinositide 3-kinase in T lymphocytes. J. Immunol. 163, 5954–5963 (1999).
Liu, Q. H. et al. HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation. Proc. Natl Acad. Sci. USA 97, 4832–4837 (2000).
Chang, Y. et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266, 1865–1869 (1994).
Moore, P. S. & Chang, Y. Molecular virology of Kaposi's sarcoma-associated herpesvirus. Philos. Trans. R. Soc. Lond. B. 356, 499–516 (2001).
Dourmishev, L. A., Dourmishev, A. L., Palmeri, D., Schwartz, R. A. & Lukac, D. M. Molecular genetics of Kaposi's sarcoma-associated herpesvirus (human herpesvirus-8) epidemiology and pathogenesis. Microbiol. Mol. Biol. Rev. 67, 175–212 (2003).
Bais, C. et al. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391, 86–89 (1998).
Arvanitakis, L., Geras-Raaka, E., Varma, A., Gershengorn, M. C. & Cesarman, E. Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 385, 347–350 (1997). References 55 and 56 provide the first evidence that the Kaposi's sarcoma GPCR harbours transforming potential and promotes the growth of endothelial cells through the release of angiogenic factors.
Cesarman, E. et al. Kaposi's sarcoma-associated herpesvirus contains G protein-coupled receptor and cyclin D homologs which are expressed in Kaposi's sarcoma and malignant lymphoma. J. Virol. 70, 8218–8223 (1996).
Rosenkilde, M. M., Kledal, T. N., Holst, P. J. & Schwartz, T. W. Selective elimination of high constitutive activity or chemokine binding in the human herpesvirus 8 encoded seven transmembrane oncogene ORF74. J. Biol. Chem. 275, 26309–26315 (2000).
Rosenkilde, M. M. & Schwartz, T. W. Potency of ligands correlates with affinity measured against agonist and inverse agonists but not against neutral ligand in constitutively active chemokine receptor. Mol. Pharmacol. 57, 602–609 (2000).
Gershengorn, M. C., Geras-Raaka, E., Varma, A. & Clark-Lewis, I. Chemokines activate Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor in mammalian cells in culture. J. Clin. Invest. 102, 1469–1472 (1998).
Rosenkilde, M. M., Waldhoer, M., Luttichau, H. R. & Schwartz, T. W. Virally encoded 7TM receptors. Oncogene 20, 1582–1593 (2001). An excellent review on virally encoded GPCRs.
Holst, P. J. et al. Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity. J. Clin. Invest. 108, 1789–1796 (2001).
Sodhi, A. et al. Akt plays a central role in sarcomagenesis induced by Kaposi's sarcoma herpesvirus-encoded G protein-coupled receptor. Proc. Natl Acad. Sci. USA 101, 4821–4826 (2004).
Montaner, S., Sodhi, A., Pece, S., Mesri, E. A. & Gutkind, J. S. The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor promotes endothelial cell survival through the activation of Akt/protein kinase B. Cancer Res. 61, 2641–2648 (2001).
Bais, C. et al. Kaposi's sarcoma associated herpesvirus G protein-coupled receptor immortalizes human endothelial cells by activation of the VEGF receptor-2/ KDR. Cancer Cell 3, 131–143 (2003).
Sodhi, A. et al. The Kaposi's sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1α. Cancer Res. 60, 4873–4880 (2000).
Couty, J. P., Geras-Raaka, E., Weksler, B. B. & Gershengorn, M. C. Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor signals through multiple pathways in endothelial cells. J. Biol. Chem. 276, 33805–33811 (2001).
Pati, S. et al. Activation of NF-κB by the human herpesvirus 8 chemokine receptor ORF74: evidence for a paracrine model of Kaposi's sarcoma pathogenesis. J. Virol. 75, 8660–8673 (2001).
Schwarz, M. & Murphy, P. M. Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor constitutively activates NF-κB and induces proinflammatory cytokine and chemokine production via a C-terminal signaling determinant. J. Immunol. 167, 505–513 (2001).
Montaner, S. et al. The small GTPase Rac1 links the Kaposi's sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia. Blood 104, 2903–2911 (2004).
Dadke, D., Fryer, B. H., Golemis, E. A. & Field, J. Activation of p21-activated kinase 1–nuclear factor κB signaling by Kaposi's sarcoma-associated herpes virus G protein-coupled receptor during cellular transformation. Cancer Res. 63, 8837–8847 (2003).
Polson, A. G., Wang, D., DeRisi, J. & Ganem, D. Modulation of host gene expression by the constitutively active G protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus. Cancer Res. 62, 4525–4530 (2002).
Cannon, M., Philpott, N. J. & Cesarman, E. The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor has broad signaling effects in primary effusion lymphoma cells. J. Virol. 77, 57–67 (2003).
Cannon, M. L. & Cesarman, E. The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells. Oncogene 23, 514–523 (2004).
Pati, S. et al. Human herpesvirus 8-encoded vGPCR activates nuclear factor of activated T cells and collaborates with human immunodeficiency virus type 1 Tat. J. Virol. 77, 5759–5773 (2003).
Hideshima, T. et al. Characterization of signaling cascades triggered by human interleukin-6 versus Kaposi's sarcoma-associated herpes virus-encoded viral interleukin 6. Clin. Cancer Res. 6, 1180–1189 (2000).
Fortunato, E. A., McElroy, A. K., Sanchez, I. & Spector, D. H. Exploitation of cellular signaling and regulatory pathways by human cytomegalovirus. Trends Microbiol. 8, 111–119 (2000).
Schwartz, S. M., Campbell, G. R. & Campbell, J. H. Replication of smooth muscle cells in vascular disease. Circ. Res. 58, 427–444 (1986).
Chee, M. S., Satchwell, S. C., Preddie, E., Weston, K. M. & Barrell, B. G. Human cytomegalovirus encodes three G protein-coupled receptor homologues. Nature 344, 774–777 (1990).
Pleskoff, O. et al. Identification of a chemokine receptor encoded by human cytomegalovirus as a cofactor for HIV-1 entry. Science 276, 1874–1878 (1997).
Casarosa, P. et al. Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28. J. Biol. Chem. 276, 1133–1137 (2001).
Waldhoer, M., Kledal, T. N., Farrell, H. & Schwartz, T. W. Murine cytomegalovirus (CMV) M33 and human CMV US28 receptors exhibit similar constitutive signaling activities. J. Virol. 76, 8161–8168 (2002).
Bodaghi, B. et al. Chemokine sequestration by viral chemoreceptors as a novel viral escape strategy: withdrawal of chemokines from the environment of cytomegalovirus-infected cells. J. Exp. Med. 188, 855–866 (1998).
Minisini, R. et al. Constitutive inositol phosphate formation in cytomegalovirus-infected human fibroblasts is due to expression of the chemokine receptor homologue pUS28. J. Virol. 77, 4489–4501 (2003).
Casarosa, P. et al. Identification of the first nonpeptidergic inverse agonist for a constitutively active viral-encoded G protein-coupled receptor. J. Biol. Chem. 278, 5172–5178 (2003). Reports the first synthetic antagonist for a viral GPCR.
Streblow, D. N. et al. Human cytomegalovirus chemokine receptor US28-induced smooth muscle cell migration is mediated by focal adhesion kinase and Src. J. Biol. Chem. 278, 50456–50465 (2003).
Streblow, D. N. et al. The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. Cell 99, 511–520 (1999). Shows that HCMV US28, a viral GPCR, can induce the migration of smooth muscle cells, providing a molecular basis for the correlative evidence that links HCMV to the acceleration of vascular disease, including atherosclerosis.
Billstrom, M. A., Johnson, G. L., Avdi, N. J. & Worthen, G. S. Intracellular signaling by the chemokine receptor US28 during human cytomegalovirus infection. J. Virol. 72, 5535–5544 (1998).
Casarosa, P. et al. Constitutive signaling of the human cytomegalovirus-encoded receptor UL33 differs from that of its rat cytomegalovirus homolog R33 by promiscuous activation of G proteins of the Gq, Gi, and Gs classes. J. Biol. Chem. 278, 50010–50023 (2003).
Dockrell, D. H. Human herpesvirus 6: molecular biology and clinical features. J. Med. Microbiol. 52, 5–18 (2003).
Isegawa, Y., Ping, Z., Nakano, K., Sugimoto, N. & Yamanishi, K. Human herpesvirus 6 open reading frame U12 encodes a functional β-chemokine receptor. J. Virol. 72, 6104–6112 (1998).
Nakano, K. et al. Human herpesvirus 7 open reading frame U12 encodes a functional β-chemokine receptor. J. Virol. 77, 8108–8115 (2003).
Milne, R. S. et al. RANTES binding and down-regulation by a novel human herpesvirus-6 β chemokine receptor. J. Immunol. 164, 2396–2404 (2000).
Birkenbach, M., Josefsen, K., Yalamanchili, R., Lenoir, G. & Kieff, E. Epstein–Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors. J. Virol. 67, 2209–2220 (1993).
Burgstahler, R., Kempkes, B., Steube, K. & Lipp, M. Expression of the chemokine receptor BLR2/EBI1 is specifically transactivated by Epstein–Barr virus nuclear antigen 2. Biochem. Biophys. Res. Commun. 215, 737–743 (1995).
Nakayama, T. et al. Human B cells immortalized with Epstein–Barr virus upregulate CCR6 and CCR10 and downregulate CXCR4 and CXCR5. J. Virol. 76, 3072–3077 (2002).
Tilton, B. et al. Signal transduction by CXC chemokine receptor 4. Stromal cell-derived factor 1 stimulates prolonged protein kinase B and extracellular signal-regulated kinase 2 activation in T lymphocytes. J. Exp. Med. 192, 313–324 (2000).
Adachi, S., Kuwata, T., Miyaike, M. & Iwata, M. Induction of CCR7 expression in thymocytes requires both ERK signal and Ca2+ signal. Biochem. Biophys. Res. Commun. 288, 1188–1193 (2001).
Stein, J. V. et al. CCR7-mediated physiological lymphocyte homing involves activation of a tyrosine kinase pathway. Blood 101, 38–44 (2003).
Bardi, G., Niggli, V. & Loetscher, P. Rho kinase is required for CCR7-mediated polarization and chemotaxis of T lymphocytes. FEBS Lett. 542, 79–83 (2003).
Yanagawa, Y. & Onoe, K. CCR7 ligands induce rapid endocytosis in mature dendritic cells with concomitant up-regulation of Cdc42 and Rac activities. Blood 101, 4923–4929 (2003).
Hasegawa, H., Utsunomiya, Y., Yasukawa, M., Yanagisawa, K. & Fujita, S. Induction of G protein-coupled peptide receptor EBI 1 by human herpesvirus 6 and 7 infection in CD4+ T cells. J. Virol. 68, 5326–5329 (1994).
Alcami, A. Viral mimicry of cytokines, chemokines and their receptors. Nature Rev. Immunol. 3, 36–50 (2003). A comprehensive review on viral cytokines, chemokines, and chemokine-binding proteins, and how they affect the function of the immune system.
Najarro, P., Lee, H. J., Fox, J., Pease, J. & Smith, G. L. Yaba-like disease virus protein 7L is a cell-surface receptor for chemokine CCL1. J. Gen. Virol. 84, 3325–3336 (2003).
Endres, M. J., Garlisi, C. G., Xiao, H., Shan, L. & Hedrick, J. A. The Kaposi's sarcoma-related herpesvirus (KSHV)-encoded chemokine vMIP-I is a specific agonist for the CC chemokine receptor (CCR)8. J. Exp. Med. 189, 1993–1998 (1999).
Dairaghi, D. J., Fan, R. A., McMaster, B. E., Hanley, M. R. & Schall, T. J. HHV8-encoded vMIP-I selectively engages chemokine receptor CCR8. Agonist and antagonist profiles of viral chemokines. J. Biol. Chem. 274, 21569–21574 (1999).
Haque, N. S., Fallon, J. T., Taubman, M. B. & Harpel, P. C. The chemokine receptor CCR8 mediates human endothelial cell chemotaxis induced by I-309 and Kaposi sarcoma herpesvirus-encoded vMIP-I and by lipoprotein(a)-stimulated endothelial cell conditioned medium. Blood 97, 39–45 (2001).
Liu, C., Okruzhnov, Y., Li, H. & Nicholas, J. Human herpesvirus 8 (HHV-8)-encoded cytokines induce expression of and autocrine signaling by vascular endothelial growth factor (VEGF) in HHV-8-infected primary-effusion lymphoma cell lines and mediate VEGF-independent antiapoptotic effects. J. Virol. 75, 10933–10940 (2001).
Louahed, J. et al. CCR8-dependent activation of the RAS/MAPK pathway mediates anti-apoptotic activity of I-309/ CCL1 and vMIP-I. Eur. J. Immunol. 33, 494–501 (2003).
Kledal, T. N. et al. A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science 277, 1656–1659 (1997).
Boshoff, C. et al. Angiogenic and HIV-inhibitory functions of KSHV-encoded chemokines. Science 278, 290–294 (1997).
Sozzani, S. et al. The viral chemokine macrophage inflammatory protein-II is a selective Th2 chemoattractant. Blood 92, 4036–4039 (1998).
Geras-Raaka, E., Varma, A., Clark-Lewis, I. & Gershengorn, M. C. Kaposi's sarcoma-associated herpesvirus (KSHV) chemokine vMIP-II and human SDF-1α inhibit signaling by KSHV G protein-coupled receptor. Biochem. Biophys. Res. Commun. 253, 725–727 (1998).
Stine, J. T. et al. KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells. Blood 95, 1151–1157 (2000).
Penfold, M. E. et al. Cytomegalovirus encodes a potent α chemokine. Proc. Natl Acad. Sci. USA 96, 9839–9844 (1999).
Saederup, N., Lin, Y. C., Dairaghi, D. J., Schall, T. J. & Mocarski, E. S. Cytomegalovirus-encoded β chemokine promotes monocyte-associated viremia in the host. Proc. Natl Acad. Sci. USA 96, 10881–10886 (1999).
Atta-ur-Rahman, Harvey, K. & Siddiqui, R. A. Interleukin-8: an autocrine inflammatory mediator. Curr. Pharm. Des. 5, 241–253 (1999).
Zou, P. et al. Human herpesvirus 6 open reading frame U83 encodes a functional chemokine. J. Virol. 73, 5926–5933 (1999).
Krathwohl, M. D., Hromas, R., Brown, D. R., Broxmeyer, H. E. & Fife, K. H. Functional characterization of the C—C chemokine-like molecules encoded by molluscum contagiosum virus types 1 and 2. Proc. Natl Acad. Sci. USA 94, 9875–9880 (1997).
Luttichau, H. R. et al. A highly selective CC chemokine receptor (CCR)8 antagonist encoded by the poxvirus molluscum contagiosum. J. Exp. Med. 191, 171–180 (2000).
Luttichau, H. R., Lewis, I. C., Gerstoft, J. & Schwartz, T. W. The herpesvirus 8-encoded chemokine vMIP-II, but not the poxvirus-encoded chemokine MC148, inhibits the CCR10 receptor. Eur. J. Immunol. 31, 1217–1220 (2001).
Seet, B. T. & McFadden, G. Viral chemokine-binding proteins. J. Leukoc. Biol. 72, 24–34 (2002).
Graham, K. A. et al. The T1/35kDa family of poxvirus-secreted proteins bind chemokines and modulate leukocyte influx into virus-infected tissues. Virology 229, 12–24 (1997).
Lalani, A. S. et al. The purified myxoma virus γ interferon receptor homolog M-T7 interacts with the heparin-binding domains of chemokines. J. Virol. 71, 4356–4363 (1997).
Lalani, A. S. et al. Role of the myxoma virus soluble CC-chemokine inhibitor glycoprotein, M-T1, during myxoma virus pathogenesis. Virology 256, 233–245 (1999).
Parry, C. M. et al. A broad spectrum secreted chemokine binding protein encoded by a herpesvirus. J. Exp. Med. 191, 573–578 (2000).
van Berkel, V. et al. Identification of a gammaherpesvirus selective chemokine binding protein that inhibits chemokine action. J. Virol. 74, 6741–6747 (2000).
Bridgeman, A., Stevenson, P. G., Simas, J. P. & Efstathiou, S. A secreted chemokine binding protein encoded by murine gammaherpesvirus-68 is necessary for the establishment of a normal latent load. J. Exp. Med. 194, 301–312 (2001).
van Berkel, V. et al. Critical role for a high-affinity chemokine-binding protein in γ-herpesvirus-induced lethal meningitis. J. Clin. Invest. 109, 905–914 (2002).
Meanwell, N. A. & Kadow, J. F. Inhibitors of the entry of HIV into host cells. Curr. Opin. Drug Discov. Devel. 6, 451–461 (2003).
Yeagle, P. L. & Albert, A. D. A conformational trigger for activation of a G protein by a G protein-coupled receptor. Biochemistry 42, 1365–1368 (2003).
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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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DOI: https://doi.org/10.1038/nrm1529
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