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Integrin αvβ3 is a coreceptor for human cytomegalovirus

Nature Medicine volume 11, pages 515–521 (2005)Cite this article

Abstract

Human cytomegalovirus (HCMV) is a widespread opportunistic pathogen that causes birth defects in newborns and severe disease in immunocompromised individuals. The broad tropism of HCMV infection suggests that it uses multiple receptors. We recently showed that the epidermal growth factor receptor (EGFR) serves as a receptor for HCMV. Here we show that HCMV also uses integrin αvβ3 as a coreceptor. Upon infection, HCMV glycoproteins gB and gH independently bind to EGFR and αvβ3, respectively, to initiate viral entry and signaling. αvβ3 then translocates to lipid rafts where it interacts with EGFR to induce coordinated signaling. The coordination between EGFR and αvβ3 is essential for the early events of HCMV infection, including viral entry, RhoA downregulation, stress-fiber disassembly and viral nuclear trafficking. Our findings support a model in which EGFR and αvβ3 work together as coreceptors for HCMV entry and signaling. This discovery is fundamental to understanding HCMV pathogenesis and developing treatment strategies targeted to viral receptors.

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Figure 1: Both αvβ3 and EGFR are required for HCMV infection, and HCMV binds both EGFR and αvβ3 independently.
Figure 2: Coordinated signaling between EGFR and αvβ3 is generated when both αvβ3 and EGFR are activated through gH and gB, respectively.
Figure 3: HCMV induces the formation of an EGFR-αvβ3 complex when both αvβ3 and EGFR are activated.
Figure 4: The lipid raft microdomain is involved in regulating HCMV-induced formation of EGFR-αvβ3 complex and coordination of signaling.
Figure 5: Coordination of PI3-K signaling and Src signaling within lipid rafts is required for HCMV entry.
Figure 6: Coordination between EGFR- and αvβ3-mediated signaling is required for HCMV-induced downregulation of RhoA activity, disruption of stress fibers and virus nuclear translocation.

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Acknowledgements

We are grateful to D. Clemmons for β3 and mutated β3 plasmids. We thank N. Raab-Traub, J. S. Pagano and D. Evers for discussion and critical review of this manuscript. This study was supported by Public Health Service research grants AI47468 from the National Institute of Allergy and Infectious Diseases and CA 19014 from the National Cancer Institute, US National Institutes of Health.

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Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, CB#7295, Lineberger Building, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Xin Wang, Shu-Mei Huong & Eng-Shang Huang

  2. Department of Neurology, Bioinformatics Building, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    David Y Huang

  3. Department of Medicine and Department of Microbiology and Immunology, Bioinformatics Building, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Eng-Shang Huang

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Correspondence to Eng-Shang Huang.

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Supplementary information

Supplementary Fig. 1

HCMV, but not HSV, induces transient interaction between EGFR and αvβ3. (PDF 26 kb)

Supplementary Fig. 2

RhoA signaling is not essential for HCMV entry. (PDF 29 kb)

Supplementary Fig. 3

A proposed model for the initiation of HCMV infection: receptor binding and signaling. (PDF 155 kb)

Supplementary Fig. 4

Integrin β1 can substitute for β3 in facilitating HCMV infection. (PDF 30 kb)

Supplementary Fig. 5

Analysis of the purified HCMV virions by SDS-polyacrylaide gel electrophoresis and electron microscopy. (PDF 56 kb)

Supplementary Methods (PDF 26 kb)

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Wang, X., Huang, D., Huong, SM. et al. Integrin αvβ3 is a coreceptor for human cytomegalovirus. Nat Med 11, 515–521 (2005). https://doi.org/10.1038/nm1236

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