Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus


Human cytomegalovirus (HCMV) is a widespread opportunistic herpesvirus that causes severe and fatal diseases in immune-compromised individuals, including organ transplant recipients and individuals with AIDS1. It is also a leading cause of virus-associated birth defects and is associated with atherosclerosis and coronary restenosis1,2,3. HCMV initiates infection and intracellular signalling by binding to its cognate cellular receptors4,5 and by activating several signalling pathways including those mediated by mitogen-activated protein kinase5,6,7, phosphatidylinositol-3-OH kinase8, interferons5,9, and G proteins10. But a cellular receptor responsible for viral entry and HCMV-induced signalling has yet to be identified. Here we show that HCMV infects cells by interacting with epidermal growth factor receptor (EGFR) and inducing signalling. Transfecting EGFR-negative cells with an EGFR complementary DNA renders non-susceptible cells susceptible to HCMV. Ligand displacement and crosslinking analyses show that HCMV interacts with EGFR through gB, its principal envelope glycoprotein. gB preferentially binds EGFR and EGFR–ErbB3 oligomeric molecules in Chinese hamster ovary cells transfected with erbB family cDNAs. Taken together, these data indicate that EGFR is a necessary component for HCMV-triggered signalling and viral entry.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Activation of EGFR, PI(3)K and PLC-γ and Ca2+ mobilization by HCMV infection of human fibroblast HEL cells.
Figure 2: HCMV infection and activation of the PI(3)K kinase pathway require EGFR expression.
Figure 3: HCMV directly binds EGFR through gB.
Figure 4: As an EGFR ligand, gB induces receptor phosphorylation and viral gene expression in HCMV-infected CHO cells transfected with erbB1 (B1), erbB2 (B2), erbB3 (B3) and erbB4 (B4).


  1. 1

    Huang, E.-S. & Kowalik, T. F. in Molecular Aspects of Human Cytomegalovirus Diseases (eds Becker, Y., Darai, G. & Huang, E. S.) 1–45 (Springer, Berlin, 1993)

    Google Scholar 

  2. 2

    Melnick, J. L., Adam, E. & Debakey, M. E. Cytomegalovirus and atherosclerosis. Eur. Heart J. 14 (suppl. K), 30–38 (1993)

    PubMed  Google Scholar 

  3. 3

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

    ADS  CAS  Article  Google Scholar 

  4. 4

    Yurochko, A. D. et al. The human cytomegalovirus UL55 (gB) and UL75 (gH) glycoprotein ligands initiate the rapid activation of Sp1 and NF-κB during infection. J. Virol. 71, 5051–5059 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    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)

    CAS  Article  Google Scholar 

  6. 6

    Johnson, R. A., Huong, S. M. & Huang, E. S. Activation of the mitogen-activated protein kinase p38 by human cytomegalovirus infection through two distinct pathways: a novel mechanism for activation of p38. J. Virol. 74, 1158–1167 (2000)

    CAS  Article  Google Scholar 

  7. 7

    Johnson, R. A., Ma, X. L., Yurochko, A. D. & Huang, E. S. The role of MKK1/2 kinase activity in human cytomegalovirus infection. J. Gen. Virol. 82, 493–497 (2001)

    CAS  Article  Google Scholar 

  8. 8

    Johnson, R. A., Wang, X., Ma, X. L., Huong, S. M. & Huang, E. S. 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)

    CAS  Article  Google Scholar 

  9. 9

    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)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Shibutani, T. et al. Pertussis toxin-sensitive G proteins as mediators of the signal transduction pathways activated by cytomegalovirus infection of smooth muscle cells. J. Clin. Invest. 100, 2054–2061 (1997)

    CAS  Article  Google Scholar 

  11. 11

    Olayioye, M. A., Neve, R. M., Lane, H. A. & Hynes, N. E. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 19, 3159–3167 (2000)

    CAS  Article  Google Scholar 

  12. 12

    Earp, H. S., Dawson, T. L., Li, X. & Yu, H. Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research. Breast Cancer Res. Treat. 35, 115–132 (1995)

    CAS  Article  Google Scholar 

  13. 13

    Riese, D. J. & Stern, D. F. Specificity within the EGF family/ErbB receptor family signaling network. BioEssays 20, 41–48 (1998)

    Article  Google Scholar 

  14. 14

    Alroy, I. & Yarden, Y. The ErbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand–receptor interactions. FEBS Lett. 410, 83–86 (1997)

    CAS  Article  Google Scholar 

  15. 15

    Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 103, 211–225 (2000)

    CAS  Article  Google Scholar 

  16. 16

    Yarden, Y. & Schlessinger, J. Epidermal growth factor induces rapid, reversible aggregation of the purified epidermal growth factor receptor. Biochemistry 26, 1443–1451 (1987)

    CAS  Article  Google Scholar 

  17. 17

    Ullrich, A. & Schlessinger, J. Signal transduction by receptors with tyrosine kinase activity. Cell 61, 203–212 (1990)

    CAS  Article  Google Scholar 

  18. 18

    Baulida, J., Kraus, M. H., Alimandi, M., Di Fiore, P. P. & Carpenter, G. All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. J. Biol. Chem. 271, 5251–5257 (1996)

    CAS  Article  Google Scholar 

  19. 19

    Peles, E. & Yarden, Y. Neu and its ligands: from an oncogene to neural factors. BioEssays 15, 815–824 (1993)

    CAS  Article  Google Scholar 

  20. 20

    Prenzel, N., Fischer, O. M., Streit, S., Hart, S. & Ullrich, A. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr. Relat. Cancer 8, 11–31 (2001)

    CAS  Article  Google Scholar 

  21. 21

    Tvorogov, D. & Carpenter, G. EGF-dependent association of phospholipase C-γ1 with c-Cbl. Exp. Cell Res. 277, 86–94 (2002)

    CAS  Article  Google Scholar 

  22. 22

    Kraus, M. H., Popescu, N. C., Amsbaugh, S. C. & King, C. R. Overexpression of the EGF receptor-related proto-oncogene erbB-2 in human mammary tumor cell lines by different molecular mechanisms. EMBO J. 6, 605–610 (1987)

    CAS  Article  Google Scholar 

  23. 23

    Tzahar, E. et al. Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network. EMBO J. 17, 5948–5963 (1998)

    CAS  Article  Google Scholar 

  24. 24

    Tzahar, E. et al. Bivalence of EGF-like ligands drives the ErbB signaling network. EMBO J. 16, 4938–4950 (1997)

    CAS  Article  Google Scholar 

  25. 25

    Compton, T., Nepomuceno, R. R. & Nowlin, D. M. Human cytomegalovirus penetrates host cells by pH-independent fusion at the cell surface. Virology 191, 387–395 (1992)

    CAS  Article  Google Scholar 

  26. 26

    Pietropaolo, R. L. & Compton, T. Direct interaction between human cytomegalovirus glycoprotein B and cellular annexin II. J. Virol. 71, 9803–9807 (1997)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Fairley, J. A., Baillie, J., Bain, M. & Sinclair, J. H. Human cytomegalovirus infection inhibits epidermal growth factor (EGF) signalling by targeting EGF receptors. J. Gen. Virol. 83, 2803–2810 (2002)

    CAS  Article  Google Scholar 

  28. 28

    Miyazawa, N. et al. Fiber swap between adenovirus subgroups B and C alters intracellular trafficking of adenovirus gene transfer vectors. J. Virol. 73, 6056–6065 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Kanda, S. et al. Phosphatidylinositol 3′-kinase-independent p70 S6 kinase activation by fibroblast growth factor receptor-1 is important for proliferation but not differentiation of endothelial cells. J. Biol. Chem. 272, 23347–23353 (1997)

    CAS  Article  Google Scholar 

  30. 30

    Sexl, V. et al. Stimulation of the mitogen-activated protein kinase via the A2A- adenosine receptor in primary human endothelial cells. J. Biol. Chem. 272, 5792–5799 (1997)

    CAS  Article  Google Scholar 

Download references


We thank S. Kenney, D. Y. Huang, B. Y. Huang, D. Evers, A. Gartner, A. T. Pelletier and J. S. Pagano for discussion, technical assistance and critically reading the manuscript. This work was supported by grants from the National Institutes of Health (to E.-S. H.).

Author information



Corresponding author

Correspondence to Eng-Shang Huang.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, X., Huong, S., Chiu, M. et al. Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus. Nature 424, 456–461 (2003). https://doi.org/10.1038/nature01818

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.