Access

Letter

Nature 455, 391-395 (18 September 2008) | doi:10.1038/nature07209; Received 15 May 2008; Accepted 25 June 2008; Published online 13 August 2008

Open Innovation Challenges

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

Liliana Soroceanu1, Armin Akhavan1 & Charles S. Cobbs1,2

  1. Department of Neurosciences, California Pacific Medical Center Research Institute, Suite 220, 475 Brannan Street, San Francisco, California 94107, USA
  2. Department of Neurological Surgery, University of California, San Francisco, 787 Moffitt, 505 Parnassus Avenue, San Francisco, California 94143, USA

Correspondence to: Charles S. Cobbs1,2 Correspondence and requests for materials should be addressed to C.C. (Email: charles.cobbs@gmail.com).

Top

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-alpha receptor (PDGFR-alpha) 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-alpha 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-alpha 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-alpha 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-alpha was competitively inhibited by pretreatment with PDGF-AA. We further demonstrate that HCMV glycoprotein B directly interacts with PDGFR-alpha, resulting in receptor tyrosine phosphorylation, and that glycoprotein B neutralizing antibodies13 inhibit HCMV-induced PDGFR-alpha phosphorylation. Taken together, these data indicate that PDGFR-alpha is a critical receptor required for HCMV infection, and thus a target for novel anti-viral therapies.