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Platelet-derived growth factor-α receptor activation is required for human cytomegalovirus infection

Nature volume 455, pages 391–395 (2008)Cite this article

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous human herpesvirus that can cause life-threatening disease in the fetus and the immunocompromised host1. Upon attachment to the cell, the virus induces robust inflammatory, interferon- and growth-factor-like signalling2,3,4,5,6,7,8,9. The mechanisms facilitating viral entry and gene expression are not clearly understood4. Here we show that platelet-derived growth factor-α receptor (PDGFR-α) is specifically phosphorylated by both laboratory and clinical isolates of HCMV in various human cell types, resulting in activation of the phosphoinositide-3-kinase (PI(3)K) signalling pathway. Upon stimulation by HCMV, tyrosine-phosphorylated PDGFR-α associated with the p85 regulatory subunit of PI(3)K and induced protein kinase B (also known as Akt) phosphorylation, similar to the genuine ligand, PDGF-AA. Cells in which PDGFR-α was genetically deleted10 or functionally blocked were non-permissive to HCMV entry, viral gene expression or infectious virus production. Re-introducing human PDGFRA gene into knockout cells restored susceptibility to viral entry and essential viral gene expression. Blockade of receptor function with a humanized PDGFR-α blocking antibody (IMC-3G3)11 or targeted inhibition of its kinase activity with a small molecule (Gleevec)12 completely inhibited HCMV viral internalization and gene expression in human epithelial, endothelial and fibroblast cells. Viral entry in cells harbouring endogenous PDGFR-α was competitively inhibited by pretreatment with PDGF-AA. We further demonstrate that HCMV glycoprotein B directly interacts with PDGFR-α, resulting in receptor tyrosine phosphorylation, and that glycoprotein B neutralizing antibodies13 inhibit HCMV-induced PDGFR-α phosphorylation. Taken together, these data indicate that PDGFR-α is a critical receptor required for HCMV infection, and thus a target for novel anti-viral therapies.

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Figure 1: HCMV induces tyrosine phosphorylation of human PDGFR-α.
Figure 2: HCMV activates the PI(3)K/Akt pathway in a PDGFR-α-dependent manner.
Figure 3: Human PDGFR-α is required for HCMV entry, IE1 expression and infectious virus production.
Figure 4: HCMV Glycoprotein B binds and activates PDGFR-α.

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References

  1. Britt, W. J. & Alford, C. A. Fields Virology 3rd edn (Raven Press, 1996)

    Google Scholar 

  2. Andreoni, K. A., Wang, X., Huang, S. M. & Huang, E. S. Human cytomegalovirus hyperimmune globulin not only neutralizes HCMV infectivity, but also inhibits HCMV-induced intracellular NF-κB, Sp1, and PI3-K signaling pathways. J. Med. Virol. 67, 33–40 (2002)

    Article  CAS  Google Scholar 

  3. Boyle, K. A., Pietropaolo, R. L. & Compton, T. Engagement of the cellular receptor for glycoprotein B of human cytomegalovirus activates the interferon-responsive pathway. Mol. Cell. Biol. 19, 3607–3613 (1999)

    Article  CAS  Google Scholar 

  4. Compton, T. Receptors and immune sensors: the complex entry path of human cytomegalovirus. Trends Cell Biol. 14, 5–8 (2004)

    Article  CAS  Google Scholar 

  5. Netterwald, J. R. et al. Postattachment events associated with viral entry are necessary for induction of interferon-stimulated genes by human cytomegalovirus. J. Virol. 78, 6688–6691 (2004)

    Article  CAS  Google Scholar 

  6. Ozato, K., Tailor, P. & Kubota, T. The interferon regulatory factor family in host defense: mechanism of action. J. Biol. Chem. 282, 20065–20069 (2007)

    Article  CAS  Google Scholar 

  7. Simmen, K. A. et al. Global modulation of cellular transcription by human cytomegalovirus is initiated by viral glycoprotein B. Proc. Natl Acad. Sci. USA 98, 7140–7145 (2001)

    Article  ADS  CAS  Google Scholar 

  8. Yurochko, A. D. et al. Induction of the transcription factor Sp1 during human cytomegalovirus infection mediates upregulation of the p65 and p105/p50 NF-κB promoters. J. Virol. 71, 4638–4648 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhu, H., Cong, J. P. & Shenk, T. Use of differential display analysis to assess the effect of human cytomegalovirus infection on the accumulation of cellular RNAs: induction of interferon-responsive RNAs. Proc. Natl Acad. Sci. USA 94, 13985–13990 (1997)

    Article  ADS  CAS  Google Scholar 

  10. Andrews, A. et al. Platelet-derived growth factor plays a key role in proliferative vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 40, 2683–2689 (1999)

    CAS  PubMed  Google Scholar 

  11. Loizos, N. et al. Targeting the platelet-derived growth factor receptor alpha with a neutralizing human monoclonal antibody inhibits the growth of tumor xenografts: implications as a potential therapeutic target. Mol. Cancer Ther. 4, 369–379 (2005)

    CAS  PubMed  Google Scholar 

  12. Sandler, C. et al. Imatinib mesylate inhibits platelet derived growth factor stimulated proliferation of rheumatoid synovial fibroblasts. Biochem. Biophys. Res. Commun. 347, 31–35 (2006)

    Article  CAS  Google Scholar 

  13. Britt, W. J. Neutralizing antibodies detect a disulfide-linked glycoprotein complex within the envelope of human cytomegalovirus. Virology 135, 369–378 (1984)

    Article  CAS  Google Scholar 

  14. Waltenberger, J. et al. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J. Biol. Chem. 269, 26988–26995 (1994)

    CAS  PubMed  Google Scholar 

  15. Feire, A. L., Koss, H. & Compton, T. Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain. Proc. Natl Acad. Sci. USA 101, 15470–15475 (2004)

    Article  ADS  CAS  Google Scholar 

  16. Cooray, S. The pivotal role of phosphatidylinositol 3-kinase-Akt signal transduction in virus survival. J. Gen. Virol. 85, 1065–1076 (2004)

    Article  CAS  Google Scholar 

  17. Wang, X., Huang, D. Y., Huong, S. M. & Huang, E. S. Integrin αvβ3 is a coreceptor for human cytomegalovirus. Nature Med. 11, 515–521 (2005)

    Article  CAS  Google Scholar 

  18. Wang, X. et al. Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus. Nature 424, 456–461 (2003)

    Article  ADS  CAS  Google Scholar 

  19. Cobbs, C. S. et al. Human cytomegalovirus induces cellular tyrosine kinase signaling and promotes glioma cell invasiveness. J. Neurooncol. 85, 271–280 (2007)

    Article  CAS  Google Scholar 

  20. Isaacson, M. K., Feire, A. L. & Compton, T. Epidermal growth factor receptor is not required for human cytomegalovirus entry or signaling. J. Virol. 81, 6241–6247 (2007)

    Article  CAS  Google Scholar 

  21. Murphy, E. et al. Coding potential of laboratory and clinical strains of human cytomegalovirus. Proc. Natl Acad. Sci. USA 100, 14976–14981 (2003)

    Article  ADS  CAS  Google Scholar 

  22. Johnson, R. A. et al. Human cytomegalovirus up-regulates the phosphatidylinositol 3-kinase (PI3-K) pathway: inhibition of PI3-K activity inhibits viral replication and virus-induced signaling. J. Virol. 75, 6022–6032 (2001)

    Article  CAS  Google Scholar 

  23. English, E. P., Chumanov, R. S., Gellman, S. H. & Compton, T. Rational development of beta-peptide inhibitors of human cytomegalovirus entry. J. Biol. Chem. 281, 2661–2667 (2006)

    Article  CAS  Google Scholar 

  24. Gredmark, S. et al. Human cytomegalovirus downregulates expression of receptors for platelet-derived growth factor by smooth muscle cells. J. Virol. 81, 5112–5120 (2007)

    Article  CAS  Google Scholar 

  25. Murphy, E. A., Streblow, D. N., Nelson, J. A. & Stinski, M. F. The human cytomegalovirus IE86 protein can block cell cycle progression after inducing transition into the S phase of permissive cells. J. Virol. 74, 7108–7118 (2000)

    Article  CAS  Google Scholar 

  26. Boyle, K. A. & Compton, T. Receptor-binding properties of a soluble form of human cytomegalovirus glycoprotein B. J. Virol. 72, 1826–1833 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Carlson, C., Britt, W. J. & Compton, T. Expression, purification, and characterization of a soluble form of human cytomegalovirus glycoprotein B. Virology 239, 198–205 (1997)

    Article  CAS  Google Scholar 

  28. Wang, Z. et al. Recombinant modified vaccinia virus Ankara expressing a soluble form of glycoprotein B causes durable immunity and neutralizing antibodies against multiple strains of human cytomegalovirus. J. Virol. 78, 3965–3976 (2004)

    Article  CAS  Google Scholar 

  29. Thomas, B. Viruses and the Cellular Immune Response (Marcel Dekker, 1993)

    Google Scholar 

  30. Huang, E. S., Chen, S. T. & Pagano, J. S. Human cytomegalovirus. I. Purification and characterization of viral DNA. J. Virol. 12, 1473–1481 (1973)

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Isomura, H. & Stinski, M. F. The human cytomegalovirus major immediate-early enhancer determines the efficiency of immediate-early gene transcription and viral replication in permissive cells at low multiplicity of infection. J. Virol. 77, 3602–3614 (2003)

    Article  CAS  Google Scholar 

  32. Chan, G., Stinski, M. F. & Guilbert, L. J. Human cytomegalovirus-induced upregulation of intercellular cell adhesion molecule-1 on villous syncytiotrophoblasts. Biol. Reprod. 71, 797–803 (2004)

    Article  CAS  Google Scholar 

  33. Britt, W. J., Jarvis, M. A., Drummond, D. D. & Mach, M. Antigenic domain 1 is required for oligomerization of human cytomegalovirus glycoprotein B. J. Virol. 79, 4066–4079 (2005)

    Article  CAS  Google Scholar 

  34. Shimamura, M., Mach, M. & Britt, W. J. Human cytomegalovirus infection elicits a glycoprotein M (gM)/gN-specific virus-neutralizing antibody response. J. Virol. 80, 4591–4600 (2006)

    Article  CAS  Google Scholar 

  35. Li, L., Coelingh, K. L. & Britt, W. J. Human cytomegalovirus neutralizing antibody-resistant phenotype is associated with reduced expression of glycoprotein H. J. Virol. 69, 6047–6053 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Mar, E. C., Cheng, Y. C. & Huang, E. S. Effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine on human cytomegalovirus replication in vitro . Antimicrob. Agents Chemother. 24, 518–521 (1983)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M. Tallquist for the PDGFR-α knockout mouse fibroblasts, C. Heldin for the human PDGFR-α cDNA, D. Diamond for providing the soluble glycoprotein B, and N. Loizos (ImClone) for the IMC-3G3 antibody. We are grateful to W. Britt (University of Alabama at Birmingham) for viruses, glycoprotein B neutralizing antibodies and discussions. This study was supported by an institutional grant from California Pacific Medical Center Research Institute and by the Arthur Flaming Foundation.

Author Contributions L.S. and A.A. performed experiments; L.S., A.A. and C.S.C. designed experiments, analysed data and wrote the manuscript.

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Authors and Affiliations

  1. Department of Neurosciences, California Pacific Medical Center Research Institute, Suite 220, 475 Brannan Street, San Francisco, California 94107, USA,

    Liliana Soroceanu, Armin Akhavan & Charles S. Cobbs

  2. Department of Neurological Surgery, University of California, San Francisco, 787 Moffitt, 505 Parnassus Avenue, San Francisco, California 94143, USA,

    Charles S. Cobbs

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  1. Liliana Soroceanu
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Correspondence to Charles S. Cobbs.

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Soroceanu, L., Akhavan, A. & Cobbs, C. Platelet-derived growth factor-α receptor activation is required for human cytomegalovirus infection. Nature 455, 391–395 (2008). https://doi.org/10.1038/nature07209

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