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  • Review Article
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Herpesvirus-encoded GPCRs: neglected players in inflammatory and proliferative diseases?

Key Points

  • By reprogramming host cellular signalling networks, herpesvirus-encoded G protein-coupled receptors (GPCRs) may subvert cellular signalling and contribute to viral pathogenesis.

  • 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.

  • Constitutive signalling of the human cytomegalovirus-encoded GPCR US28 induces cell transformation and proliferation in in vitro and in vivo model systems.

  • US28 is present in glioblastoma tumour samples and might be a hitherto neglected target for therapeutic intervention.

  • 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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Figure 1: Role of ORF74 in the KSHV infection cycle and onset of Kaposi's sarcoma.
Figure 2: US28-mediated signalling and cellular responses that result in a proliferative, pro-angiogenic and migratory phenotype.
Figure 3: Structures of US28 inhibitors.

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References

  1. Vischer, H. F., Vink, C. & Smit, M. J. A viral conspiracy: hijacking the chemokine system through virally encoded pirated chemokine receptors. Curr. Top. Microbiol. Immunol. 303, 121–154 (2006).

    CAS  PubMed  Google Scholar 

  2. Delecluse, H. J., Feederle, R., O'Sullivan, B. & Taniere, P. Epstein Barr virus-associated tumours: an update for the attention of the working pathologist. J. Clin. Pathol. 60, 1358–1364 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Du, M. Q., Bacon, C. M. & Isaacson, P. G. Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 and lymphoproliferative disorders. J. Clin. Pathol. 60, 1350–1357 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Soderberg-Naucler, C. HCMV microinfections in inflammatory diseases and cancer. J. Clin. Virol. 41, 218–223 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. White, M. K., Gorrill, T. S. & Khalili, K. Reciprocal transactivation between HIV-1 and other human viruses. Virology 352, 1–13 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Fischer, S. A. Emerging viruses in transplantation: there is more to infection after transplant than CMV and EBV. Transplantation 86, 1327–1339 (2008).

    Article  PubMed  Google Scholar 

  7. Scholten, D. et al. Pharmacological modulation of chemokine receptor function. Br. J. Pharmacol. 165, 1617–1643 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Perlin, J. R. & Talbot, W. S. Signals on the move: chemokine receptors and organogenesis in zebrafish. Sci. STKE 2007, e45 (2007).

    Article  Google Scholar 

  9. Lazennec, G. & Richmond, A. Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends Mol. Med. 16, 133–144 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wijtmans, M., Scholten, D. J., de Esch, I. J., Smit, M. J. & Leurs, R. Therapeutic targeting of chemokine receptors by small molecules. Drug Discov. Today Technol. 9, e229–e236 (2012).

    Article  CAS  Google Scholar 

  11. Klarenbeek, A. et al. Targeting chemokines and chemokine receptors with antibodies. Drug Discov. Today Technol. 9, e237–e244 (2012).

    Article  CAS  Google Scholar 

  12. Vischer, H. F., Leurs, R. & Smit, M. J. HCMV-encoded G-protein-coupled receptors as constitutively active modulators of cellular signaling networks. Trends Pharmacol. Sci. 27, 56–63 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Smit, M. J. et al. Pharmacogenomic and structural analysis of constitutive G protein-coupled receptor activity. Annu. Rev. Pharmacol. Toxicol. 47, 53–87 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cesarman, E., Chang, Y., Moore, P. S., Said, J. W. & Knowles, D. M. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS- related body-cavity-based lymphomas. N. Engl. J. Med. 332, 1186–1191 (1995). This paper shows that KSHV is present in lymphomas of HIV-infected patients, therefore linking the virus to oncogenesis in immunocompromised individuals.

    Article  CAS  PubMed  Google Scholar 

  16. Casper, C. & Wald, A. The use of antiviral drugs in the prevention and treatment of Kaposi sarcoma, multicentric Castleman disease and primary effusion lymphoma. Curr. Top. Microbiol. Immunol. 312, 289–307 (2007).

    CAS  PubMed  Google Scholar 

  17. Mesri, E. A., Cesarman, E. & Boshoff, C. Kaposi's sarcoma and its associated herpesvirus. Nature Rev. Cancer 10, 707–719 (2010).

    Article  CAS  Google Scholar 

  18. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. Staskus, K. A. et al. Kaposi's sarcoma-associated herpesvirus gene expression in endothelial (spindle) tumor cells. J. Virol. 71, 715–719 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Boshoff, C. et al. Kaposi's sarcoma-associated herpesvirus infects endothelial and spindle cells. Nature Med. 1, 1274–1278 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. 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). This paper links the constitutive activity of ORF74 to the stimulation of cellular proliferation and paracrine signalling.

    Article  CAS  PubMed  Google Scholar 

  23. 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). This study describes the first transgenic mouse model that was used to investigate the oncogenic potential of ORF74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Guo, H. G. et al. Kaposi's sarcoma-like tumors in a human herpesvirus 8 ORF74 transgenic mouse. J. Virol. 77, 2631–2639 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. Jensen, K. K. et al. The human herpes virus 8-encoded chemokine receptor is required for angioproliferation in a murine model of Kaposi's sarcoma. J. Immunol. 174, 3686–3694 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Zhang, J., Wang, J., Wood, C., Xu, D. & Zhang, L. Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 replication and transcription activator regulates viral and cellular genes via interferon-stimulated response elements. J. Virol. 79, 5640–5652 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sandford, G., Choi, Y. B. & Nicholas, J. Role of ORF74-encoded viral G protein-coupled receptor in human herpesvirus 8 lytic replication. J. Virol. 83, 13009–13014 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chiou, C. J. et al. Patterns of gene expression and a transactivation function exhibited by the vGCR (ORF74) chemokine receptor protein of Kaposi's sarcoma-associated herpesvirus. J. Virol. 76, 3421–3439 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Montaner, S. et al. The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor as a therapeutic target for the treatment of Kaposi's sarcoma. Cancer Res. 66, 168–174 (2006). This study provides the first clear indication that ORF74 is a therapeutic target for Kaposi's sarcoma.

    Article  CAS  PubMed  Google Scholar 

  31. Glaunsinger, B. & Ganem, D. Lytic KSHV infection inhibits host gene expression by accelerating global mRNA turnover. Mol. Cell 13, 713–723 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Liang, Y. & Ganem, D. RBP-J (CSL) is essential for activation of the K14/vGPCR promoter of Kaposi's sarcoma-associated herpesvirus by the lytic switch protein RTA. J. Virol. 78, 6818–6826 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Verzijl, D. et al. Differential activation of murine herpesvirus 68- and Kaposi's sarcoma-associated herpesvirus-encoded ORF74 G protein-coupled receptors by human and murine chemokines. J. Virol. 78, 3343–3351 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rosenkilde, M. M., Waldhoer, M., Luttichau, H. R. & Schwartz, T. W. Virally encoded 7TM receptors. Oncogene 20, 1582–1593 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Kledal, T. N. et al. A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus. Science 277, 1656–1659 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  CAS  PubMed  Google Scholar 

  39. Yen-Moore, A. et al. Differential expression of the HHV-8 vGCR cellular homolog gene in AIDS-associated and classic Kaposi's sarcoma: potential role of HIV-1 Tat. Virology 267, 247–251 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. 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).

    CAS  PubMed  Google Scholar 

  41. Smit, M. J. et al. Kaposi's sarcoma-associated herpesvirus-encoded G protein-coupled receptor ORF74 constitutively activates p44/p42 MAPK and Akt via Gi and phospholipase C-dependent signaling pathways. J. Virol. 76, 1744–1752 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Martin, D. et al. PI3Kγ mediates Kaposi's sarcoma-associated herpesvirus vGPCR-induced sarcomagenesis. Cancer Cell 19, 805–813 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. Martin, M. J. et al. The Gα12/13 family of heterotrimeric G proteins and the small GTPase RhoA link the Kaposi sarcoma-associated herpes virus G protein-coupled receptor to heme oxygenase-1 expression and tumorigenesis. J. Biol. Chem. 282, 34510–34524 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Shelby, B. D. et al. Kaposi's sarcoma associated herpesvirus G-protein coupled receptor activation of cyclooxygenase-2 in vascular endothelial cells. Virol. J. 4, 87 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sharma-Walia, N. et al. COX-2/PGE2: molecular ambassadors of Kaposi's sarcoma-associated herpes virus oncoprotein-v-FLIP. Oncogenesis 1, e5 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Montaner, S. et al. The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia. Blood 104, 2903–2911 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Shepard, L. W. et al. Constitutive activation of NF-κB and secretion of IL-8 induced by the G protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus involves Gα13 and RhoA. J. Biol. Chem. i276, 45979–45987 (2001).

    Article  CAS  Google Scholar 

  49. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Martin, D., Galisteo, R., Ji, Y., Montaner, S. & Gutkind, J. S. An NF-κB gene expression signature contributes to Kaposi's sarcoma virus vGPCR-induced direct and paracrine neoplasia. Oncogene 27, 1844–1852 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Lei, X. et al. Regulation of NF-κB inhibitor IκBα and viral replication by a KSHV microRNA. Nature Cell Biol. 12, 193–199 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Ma, Q. et al. Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi's sarcoma. Proc. Natl Acad. Sci. USA 106, 8683–8688 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  53. 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).

    Article  CAS  PubMed  Google Scholar 

  54. 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).

    CAS  PubMed  Google Scholar 

  55. 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).

    Article  CAS  PubMed  Google Scholar 

  56. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vart, R. J. et al. Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6 and G-protein-coupled receptor regulate angiopoietin-2 expression in lymphatic endothelial cells. Cancer Res. 67, 4042–4051 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Depeille, P. et al. Anthrax lethal toxin inhibits growth of and vascular endothelial growth factor release from endothelial cells expressing the human herpes virus 8 viral G protein coupled receptor. Clin. Cancer Res. 13, 5926–5934 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Jham, B. C. et al. Amplification of the angiogenic signal through the activation of the TSC/mTOR/HIF axis by the KSHV vGPCR in Kaposi's sarcoma. PLoS ONE 6, e19103 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lee, D. F. & Hung, M. C. All roads lead to mTOR: integrating inflammation and tumor angiogenesis. Cell Cycle 6, 3011–3014 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Cannon, M., Cesarman, E. & Boshoff, C. K.S.H. V. G protein-coupled receptor inhibits lytic gene transcription in primary-effusion lymphoma cells via p21-mediated inhibition of Cdk2. Blood 107, 277–284 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Nador, R. G. et al. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood 88, 645–656 (1996).

    CAS  PubMed  Google Scholar 

  63. 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).

    Article  CAS  PubMed  Google Scholar 

  64. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wu, B. et al. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330, 1066–1071 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Stevens, R. C. et al. The GPCR Network: a large-scale collaboration to determine human GPCR structure and function. Nature Rev. Drug Discov. 12, 25–34 (2013).

    Article  CAS  Google Scholar 

  67. Chaisuparat, R. et al. Dual inhibition of PI3Kα and mTOR as an alternative treatment for Kaposi's sarcoma. Cancer Res. 68, 8361–8368 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cesarman, E. Gammaherpesviruses and lymphoproliferative disorders. Annu. Rev. Pathol. http://dx.doi.org/10.1146/annurev-pathol-012513-104656 (2013).

  69. Humme, S. et al. The EBV nuclear antigen 1 (EBNA1) enhances B cell immortalization several thousandfold. Proc. Natl Acad. Sci. USA 100, 10989–10994 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Johansen, L. M. et al. EBNA2 and activated Notch induce expression of BATF. J. Virol. 77, 6029–6040 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Guasparri, I., Bubman, D. & Cesarman, E. EBV LMP2A affects LMP1-mediated NF-κB signaling and survival of lymphoma cells by regulating TRAF2 expression. Blood 111, 3813–3820 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Beisser, P. S. et al. The Epstein-Barr virus BILF1 gene encodes a G protein-coupled receptor that inhibits phosphorylation of RNA-dependent protein kinase. J. Virol. 79, 441–449 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Paulsen, S. J., Rosenkilde, M. M., Eugen-Olsen, J. & Kledal, T. N. Epstein-Barr virus-encoded BILF1 is a constitutively active G protein-coupled receptor. J. Virol. 79, 536–546 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Vischer, H. F., Nijmeijer, S., Smit, M. J. & Leurs, R. Viral hijacking of human receptors through heterodimerization. Biochem. Biophys. Res. Commun. 377, 93–97 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Nijmeijer, S., Leurs, R., Smit, M. J. & Vischer, H. F. The Epstein-Barr virus-encoded G protein-coupled receptor BILF1 hetero-oligomerizes with human CXCR4, scavenges Gαi proteins, and constitutively impairs CXCR4 functioning. J. Biol. Chem. 285, 29632–29641 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Williams, B. R. PKR; a sentinel kinase for cellular stress. Oncogene 18, 6112–6120 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Walsh, D. & Mohr, I. Viral subversion of the host protein synthesis machinery. Nature Rev. Microbiol. 9, 860–875 (2011).

    Article  CAS  Google Scholar 

  78. Griffin, B. D. et al. EBV BILF1 evolved to downregulate cell surface display of a wide range of HLA class I molecules through their cytoplasmic tail. J. Immunol. 190, 1672–1684 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Vuyisich, M., Spanggord, R. J. & Beal, P. A. The binding site of the RNA-dependent protein kinase (PKR) on EBER1 RNA from Epstein-Barr virus. EMBO Rep. 3, 622–627 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Poppers, J., Mulvey, M., Perez, C., Khoo, D. & Mohr, I. Identification of a lytic-cycle Epstein-Barr virus gene product that can regulate PKR activation. J. Virol. 77, 228–236 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hislop, A. D., Taylor, G. S., Sauce, D. & Rickinson, A. B. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu. Rev. Immunol. 25, 587–617 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Haque, T. et al. Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet 360, 436–442 (2002).

    Article  PubMed  Google Scholar 

  83. Zuo, J. et al. The Epstein-Barr virus-encoded BILF1 protein modulates immune recognition of endogenously processed antigen by targeting major histocompatibility complex class I molecules trafficking on both the exocytic and endocytic pathways. J. Virol. 85, 1604–1614 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Zuo, J. et al. The Epstein-Barr virus G-protein-coupled receptor contributes to immune evasion by targeting MHC class I molecules for degradation. PLoS Pathog. 5, e1000255 (2009). This study provides data showing that that the EBV-encoded vGPCR BILF1 reduces the levels of MHC class I molecules to produce an effective immune-evasion strategy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Rowe, M. et al. Host shutoff during productive Epstein-Barr virus infection is mediated by BGLF5 and may contribute to immune evasion. Proc. Natl Acad. Sci. USA 104, 3366–3371 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hislop, A. D. et al. A CD8+ T cell immune evasion protein specific to Epstein-Barr virus and its close relatives in Old World primates. J. Exp. Med. 204, 1863–1873 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lyngaa, R. et al. Cell transformation mediated by the Epstein-Barr virus G protein-coupled receptor BILF1 is dependent on constitutive signaling. Oncogene 29, 4388–4398 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Michaelis, M., Doerr, H. W. & Cinatl, J. Jr. Oncomodulation by human cytomegalovirus: evidence becomes stronger. Med. Microbiol. Immunol. 198, 79–81 (2009).

    Article  PubMed  Google Scholar 

  89. 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).

    Article  CAS  PubMed  Google Scholar 

  90. Gao, J. L. & Murphy, P. M. Human cytomegalovirus open reading frame US28 encodes a functional beta chemokine receptor. J. Biol. Chem. 269, 28539–28542 (1994).

    CAS  PubMed  Google Scholar 

  91. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Kledal, T. N., Rosenkilde, M. M. & Schwartz, T. W. Selective recognition of the membrane-bound CX3C chemokine, fractalkine, by the human cytomegalovirus-encoded broad-spectrum receptor US28. FEBS Lett. 441, 209–214 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Casarosa, P. et al. Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28. J. Biol. Chem. 276, 1133–1137 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Moepps, B. et al. Constitutive serum response factor activation by the viral chemokine receptor homologue pUS28 is differentially regulated by Gαq/11 and Gα16 . Cell. Signall. 20, 1528–1537 (2008).

    Article  CAS  Google Scholar 

  95. 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).

    Article  CAS  PubMed  Google Scholar 

  96. Lares, A. P., Tu, C. C. & Spencer, J. V. The human cytomegalovirus US27 gene product enhances cell proliferation and alters cellular gene expression. Virus Res. 176, 312–320 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Tadagaki, K. et al. Human cytomegalovirus-encoded UL33 and UL78 heteromerize with host CCR5 and CXCR4 impairing their HIV coreceptor activity. Blood 119, 4908–4918 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Arnolds, K. L., Lares, A. P. & Spencer, J. V. The US27 gene product of human cytomegalovirus enhances signaling of host chemokine receptor CXCR4. Virology 439, 122–131 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Gruijthuijsen, Y. K. et al. The rat cytomegalovirus R33-encoded G protein-coupled receptor signals in a constitutive fashion. J. Virol. 76, 1328–1338 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Melnychuk, R. M. et al. Mouse cytomegalovirus M33 is necessary and sufficient in virus-induced vascular smooth muscle cell migration. J. Virol. 79, 10788–10795 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Farrell, H. E. et al. Identification of common mechanisms by which human and mouse cytomegalovirus seven-transmembrane receptor homologues contribute to in vivo phenotypes in a mouse model. J. Virol. 87, 4112–4117 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Farrell, H. E. et al. Partial functional complementation between human and mouse cytomegalovirus chemokine receptor homologues. J. Virol. 85, 6091–6095 (2011). This study describes the use of recombinant murine viral strains in which vGPCRs are substituted by human GPCR orthologues.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Margulies, B. J., Browne, H. & Gibson, W. Identification of the human cytomegalovirus G protein-coupled receptor homologue encoded by UL33 in infected cells and enveloped virus particles. Virology 225, 111–125 (1996).

    Article  CAS  PubMed  Google Scholar 

  104. Fraile-Ramos, A. et al. The human cytomegalovirus US28 protein is located in endocytic vesicles and undergoes constitutive endocytosis and recycling. Mol. Biol. Cell 12, 1737–1749 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Margulies, B. J. & Gibson, W. The chemokine receptor homologue encoded by US27 of human cytomegalovirus is heavily glycosylated and is present in infected human foreskin fibroblasts and enveloped virus particles. Virus Res. 123, 57–71 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Penfold, M. E., Schmidt, T. L., Dairaghi, D. J., Barry, P. A. & Schall, T. J. Characterization of the rhesus cytomegalovirus US28 locus. J. Virol. 77, 10404–10413 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Varnum, S. M. et al. Identification of proteins in human cytomegalovirus (HCMV) particles: the HCMV proteome. J. Virol. 78, 10960–10966 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. O'Connor, C. M. & Shenk, T. Human cytomegalovirus pUS27 G protein-coupled receptor homologue is required for efficient spread by the extracellular route but not for direct cell-to-cell spread. J. Virol. 85, 3700–3707 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Rowe, W. P., Hartley, J. W., Cramblett, H. G. & Mastrota, F. M. Detection of human salivary gland virus in the mouth and urine of children. Am. J. Hyg. 67, 57–65 (1958).

    CAS  PubMed  Google Scholar 

  110. Beisser, P. S. et al. The R33 G protein-coupled receptor gene of rat cytomegalovirus plays an essential role in the pathogenesis of viral infection. J. Virol. 72, 2352–2363 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Davis-Poynter, N. J. et al. Identification and characterization of a G protein-coupled receptor homolog encoded by murine cytomegalovirus. J. Virol. 71, 1521–1529 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Case, R. et al. Functional analysis of the murine cytomegalovirus chemokine receptor homologue M33: ablation of constitutive signaling is associated with an attenuated phenotype in vivo. J. Virol. 82, 1884–1898 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Cardin, R. D., Schaefer, G. C., Allen, J. R., Davis-Poynter, N. J. & Farrell, H. E. The M33 chemokine receptor homolog of murine cytomegalovirus exhibits a differential tissue-specific role during in vivo replication and latency. J. Virol. 83, 7590–7601 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Streblow, D. N. et al. Rat cytomegalovirus-accelerated transplant vascular sclerosis is reduced with mutation of the chemokine-receptor R33. Am. J. Transplant. 5, 436–442 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Oliveira, S. A. & Shenk, T. E. Murine cytomegalovirus M78 protein, a G protein-coupled receptor homologue, is a constituent of the virion and facilitates accumulation of immediate-early viral mRNA. Proc. Natl Acad. Sci. USA 98, 3237–3242 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Beisser, P. S., Grauls, G., Bruggeman, C. A. & Vink, C. Deletion of the R78 G protein-coupled receptor gene from rat cytomegalovirus results in an attenuated, syncytium-inducing mutant strain. J. Virol. 73, 7218–7230 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Kaptein, S. J. et al. The rat cytomegalovirus R78 G protein-coupled receptor gene is required for production of infectious virus in the spleen. J. Gen. Virol. 84, 2517–2530 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Michel, D. et al. The human cytomegalovirus UL78 gene is highly conserved among clinical isolates, but is dispensable for replication in fibroblasts and a renal artery organ-culture system. J. Gen. Virol. 86, 297–306 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. O'Connor, C. M. & Shenk, T. Human cytomegalovirus pUL78 G protein-coupled receptor homologue is required for timely cell entry in epithelial cells but not fibroblasts. J. Virol. 86, 11425–11433 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Tschische, P., Tadagaki, K., Kamal, M., Jockers, R. & Waldhoer, M. Heteromerization of human cytomegalovirus encoded chemokine receptors. Biochem. Pharmacol. 82, 610–619 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kuhn, D. E., Beall, C. J. & Kolattukudy, P. E. The cytomegalovirus US28 protein binds multiple CC chemokines with high affinity. Biochem. Biophys. Res. Commun. 211, 325–330 (1995).

    Article  CAS  PubMed  Google Scholar 

  122. Casarosa, P. et al. CC and CX3C chemokines differentially interact with the N terminus of the human cytomegalovirus-encoded US28 receptor. J. Biol. Chem. 280, 3275–3285 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Mokros, T. et al. Surface expression and endocytosis of the human cytomegalovirus-encoded chemokine receptor US28 is regulated by agonist-independent phosphorylation. J. Biol. Chem. 277, 45122–45128 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Miller, W. E., Houtz, D. A., Nelson, C. D., Kolattukudy, P. E. & Lefkowitz, R. J. G-protein-coupled receptor (GPCR) kinase phosphorylation and beta-arrestin recruitment regulate the constitutive signaling activity of the human cytomegalovirus US28 GPCR. J. Biol. Chem. 278, 21663–21671 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Droese, J. et al. HCMV-encoded chemokine receptor US28 employs multiple routes for internalization. Biochem. Biophys. Res. Commun. 322, 42–49 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Vieira, J., Schall, T. J., Corey, L. & Geballe, A. P. Functional analysis of the human cytomegalovirus US28 gene by insertion mutagenesis with the green fluorescent protein gene. J. Virol. 72, 8158–8165 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Billstrom, M. A., Lehman, L. A. & Scott Worthen, G. Depletion of extracellular RANTES during human cytomegalovirus infection of endothelial cells. Am. J. Respir. Cell. Mol. Biol. 21, 163–167 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. 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). This was the first identification of a low- molecular-mass compound targeting the constitutively active HCMV vGPCR US28.

    Article  CAS  PubMed  Google Scholar 

  130. Hulshof, J. W. et al. Synthesis and structure-activity relationship of the first nonpeptidergic inverse agonists for the human cytomegalovirus encoded chemokine receptor US28. J. Med. Chem. 48, 6461–6471 (2005).

    Article  CAS  PubMed  Google Scholar 

  131. Hulshof, J. W. et al. Synthesis and pharmacological characterization of novel inverse agonists acting on the viral-encoded chemokine receptor US28. Bioorg. Med. Chem. 14, 7213–7230 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Vischer, H. F. et al. Identification of novel allosteric nonpeptidergic inhibitors of the human cytomegalovirus-encoded chemokine receptor US28. Bioorg. Med. Chem. 18, 675–688 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Frascaroli, G. et al. Human cytomegalovirus subverts the functions of monocytes, impairing chemokine-mediated migration and leukocyte recruitment. J. Virol. 80, 7578–7589 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. King, C. A., Baillie, J. & Sinclair, J. H. Human cytomegalovirus modulation of CCR5 expression on myeloid cells affects susceptibility to human immunodeficiency virus type 1 infection. J. Gen. Virol. 87, 2171–2180 (2006).

    Article  CAS  PubMed  Google Scholar 

  135. Cobbs, C. S. et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 62, 3347–3350 (2002).

    CAS  PubMed  Google Scholar 

  136. Miller, W. E. et al. US28 is a potent activator of phospholipase C during HCMV infection of clinically relevant target cells. PLoS ONE 7, e50524 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Scheurer, M. E., Bondy, M. L., Aldape, K. D., Albrecht, T. & El-Zein, R. Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol. 116, 79–86 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Bhattacharjee, B., Renzette, N. & Kowalik, T. F. Genetic analysis of cytomegalovirus in malignant gliomas. J. Virol. 86, 6815–6824 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Baryawno, N. et al. Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target. J. Clin. Invest. 121, 4043–4055 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Wolmer-Solberg, N. et al. Frequent detection of human cytomegalovirus in neuroblastoma: a novel therapeutic target? Int. J. Cancer 133, 2351–2361 (2013).

    Article  CAS  PubMed  Google Scholar 

  141. Wang, X., Huang, D. Y., Huong, S. M. & Huang, E. S. Integrin αβ3 is a coreceptor for human cytomegalovirus. Nature Med. 11, 515–521 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. Wang, X., Huong, S. M., Chiu, M. L., Raab-Traub, N. & Huang, E. S. Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus. Nature 424, 456–461 (2003).

    Article  CAS  PubMed  Google Scholar 

  143. Soroceanu, L., Akhavan, A. & Cobbs, C. S. Platelet-derived growth factor-alpha receptor activation is required for human cytomegalovirus infection. Nature 455, 391–395 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  145. Zhu, H., Cong, J. P., Mamtora, G., Gingeras, T. & Shenk, T. Cellular gene expression altered by human cytomegalovirus: global monitoring with oligonucleotide arrays. Proc. Natl Acad. Sci. USA 95, 14470–14475 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Soroceanu, L. et al. Human cytomegalovirus US28 found in glioblastoma promotes an invasive and angiogenic phenotype. Cancer Res. 71, 6643–6653 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Maussang, D. et al. Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proc. Natl Acad. Sci. USA 103, 13068–13073 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Maussang, D. et al. The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2. Cancer Res. 69, 2861–2869 (2009).

    Article  CAS  PubMed  Google Scholar 

  149. Turini, M. E. & DuBois, R. N. Cyclooxygenase-2: a therapeutic target. Annu. Rev. Med. 53, 35–57 (2002).

    Article  CAS  PubMed  Google Scholar 

  150. Dziurzynski, K. et al. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol. 14, 246–255 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Soderberg-Naucler, C., Rahbar, A. & Stragliotto, G. Survival in patients with glioblastoma receiving valganciclovir. N. Engl. J. Med. 369, 985–986 (2013).

    Article  CAS  PubMed  Google Scholar 

  152. Price, R. L. et al. Cytomegalovirus contributes to glioblastoma in the context of tumor suppressor mutations. Cancer Res. 73, 3441–3450 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Dziurzynski, K. et al. Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype. Clin. Cancer Res. 17, 4642–4649 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Slinger, E. et al. HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6–STAT3 axis. Sci. Signal. 3, ra58 (2010). This was the first evidence showing that the HCMV vGPCR US28 is expressed in glioblastoma tumour samples, which is associated with the constitutive activation of the STAT3–IL-6 pathway and correlates with poor outcome in patients with HCMV-positive glioblastoma.

    Article  CAS  PubMed  Google Scholar 

  155. Wang, H. et al. Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth. Stem Cells 27, 2393–2404 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Aaronson, D. S. et al. An androgen-IL-6–Stat3 autocrine loop re-routes EGF signal in prostate cancer cells. Mol. Cell Endocrinol. 270, 50–56 (2007).

    Article  CAS  PubMed  Google Scholar 

  157. Lieblein, J. C. et al. STAT3 can be activated through paracrine signaling in breast epithelial cells. BMC Cancer 8, 302 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Botto, S. et al. IL-6 in human cytomegalovirus secretome promotes angiogenesis and survival of endothelial cells through the stimulation of survivin. Blood 117, 352–361 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Martini, M. et al. Prognostic relevance of SOCS3 hypermethylation in patients with glioblastoma multiforme. Int. J. Cancer 123, 2955–2960 (2008).

    Article  CAS  PubMed  Google Scholar 

  160. Desbaillets, I. et al. Human astrocytomas and glioblastomas express monocyte chemoattractant protein-1 (MCP-1) in vivo and in vitro. Int. J. Cancer 58, 240–247 (1994).

    Article  CAS  PubMed  Google Scholar 

  161. Harkins, L. et al. Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer. Lancet 360, 1557–1563 (2002).

    Article  CAS  PubMed  Google Scholar 

  162. Chen, H. P. et al. Human cytomegalovirus preferentially infects the neoplastic epithelium of colorectal cancer: a quantitative and histological analysis. J. Clin. Virol. 54, 240–244 (2012).

    Article  PubMed  Google Scholar 

  163. Bongers, G. et al. The cytomegalovirus-encoded chemokine receptor US28 promotes intestinal neoplasia in transgenic mice. J. Clin. Invest. 120, 3969–3978 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Mazzucchelli, L. et al. Differential in situ expression of the genes encoding the chemokines MCP-1 and RANTES in human inflammatory bowel disease. J. Pathol. 178, 201–206 (1996).

    Article  CAS  PubMed  Google Scholar 

  165. Bakker, R. A., Casarosa, P., Timmerman, H., Smit, M. J. & Leurs, R. Constitutively active Gq/11-coupled receptors enable signaling by co-expressed Gi/o-coupled receptors. J. Biol. Chem. 279, 5152–5161 (2004).

    Article  CAS  PubMed  Google Scholar 

  166. Langemeijer, E. V. et al. Constitutive beta-catenin signaling by the viral chemokine receptor US28. PloS one 7, e48935 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ullman, T., Croog, V., Harpaz, N., Sachar, D. & Itzkowitz, S. Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis. Gastroenterology 125, 1311–1319 (2003).

    Article  PubMed  Google Scholar 

  168. Bongers, G. et al. A role for the epidermal growth factor receptor signaling in development of intestinal serrated polyps in mice and humans. Gastroenterology 143, 730–740 (2012).

    Article  CAS  PubMed  Google Scholar 

  169. Speir, E. et al. Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 265, 391–394 (1994).

    Article  CAS  PubMed  Google Scholar 

  170. Melnick, J. L., Adam, E. & DeBakey, M. E. Cytomegalovirus and atherosclerosis. Arch. Immunol. Ther. Exp. 44, 297–302 (1996).

    CAS  Google Scholar 

  171. Caposio, P., Orloff, S. L. & Streblow, D. N. The role of cytomegalovirus in angiogenesis. Virus Res. 157, 204–211 (2011).

    Article  CAS  PubMed  Google Scholar 

  172. 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).

    Article  CAS  PubMed  Google Scholar 

  173. Melnychuk, R. M. et al. Human cytomegalovirus-encoded G protein-coupled receptor US28 mediates smooth muscle cell migration through Gα12 . J. Virol. 78, 8382–8391 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Vomaske, J. et al. Differential ligand binding to a human cytomegalovirus chemokine receptor determines cell type-specific motility. PLoS Pathog. 5, e1000304 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Streblow, D. N. et al. The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. Cell 99, 511–520 (1999). The first study describing the ability of the HCMV vGPCR US28 to mediate smooth muscle migration, providing a molecular basis for the correlative evidence that links HCMV to the acceleration of vascular disease.

    Article  CAS  PubMed  Google Scholar 

  176. Dumortier, J. et al. Human cytomegalovirus secretome contains factors that induce angiogenesis and wound healing. J. Virol. 82, 6524–6535 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. McMaster, B. E., Schall, T. J., Penfold, M. E., Wright, J. J. & Dairaghi, D. J. Bicyclic compounds as inhibitors of chemokine binding to US28. Patent WO03018549 (2003).

  178. McMaster, B. E., Schall, T. J., Penfold, M. E., Wright, J. J. & Dairaghi, D. J. Arylamines as inhibitors of chemokine binding to US28. Patent WO03020029 (2003).

  179. Schall, T. J., McMaster, B. E. & Dairaghi, D. J. Modulators of US28. Patent WO0217900 (2002).

  180. Schall, T. J., McMaster, B. E. & Dairaghi, D. J. Reagents and methods for the diagnosis of CMV dissemination. Patent WO0217969 (2002).

  181. Kralj, A. et al. Identification of novel allosteric modulators for the G-protein coupled US28 receptor of human cytomegalovirus. Bioorg. Med. Chem. Lett. 21, 5446–5450 (2011).

    Article  CAS  PubMed  Google Scholar 

  182. Kralj, A. et al. Development of flavonoid-based inverse agonists of the key signaling receptor US28 of human cytomegalovirus. J. Med. Chem. 56, 5019–5032 (2013).

    Article  CAS  PubMed  Google Scholar 

  183. Tan, Q. et al. Structure of the CCR5 chemokine receptor-HIV entry inhibitor maraviroc complex. Science 341, 1387–1390 (2013).

    Article  CAS  PubMed  Google Scholar 

  184. Jahnichen, S. et al. CXCR4 nanobodies (VHH-based single variable domains) potently inhibit chemotaxis and HIV-1 replication and mobilize stem cells. Proc. Natl Acad. Sci. USA 107, 20565–20570 (2010). This study describes a novel approach using llama-derived antibodies to effectively, selectively and therapeutically target GPCRs.

    Article  PubMed  PubMed Central  Google Scholar 

  185. Chang, D. K. et al. Humanization of an anti-CCR4 antibody that kills cutaneous T-cell lymphoma cells and abrogates suppression by T-regulatory cells. Mol. Cancer Ther. 11, 2451–2461 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Rajagopal, S., Rajagopal, K. & Lefkowitz, R. J. Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nature Rev. Drug Discov. 9, 373–386 (2010).

    Article  CAS  Google Scholar 

  187. Vischer, H. F., Watts, A. O., Nijmeijer, S. & Leurs, R. G protein-coupled receptors: walking hand-in-hand, talking hand-in-hand? Br. J. Pharmacol. 163, 246–260 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Montaner, S., Kufareva, I., Abagyan, R. & Gutkind, J. S. Molecular mechanisms deployed by virally encoded G protein-coupled receptors in human diseases. Annu. Rev. Pharmacol. Toxicol. 53, 331–354 (2013).

    Article  CAS  PubMed  Google Scholar 

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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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