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. Cobbs^1,2 Correspondence and requests for materials should be addressed to C.C. (Email: charles.cobbs@gmail.com).

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 signalling^{2, 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- receptor (PDGFR-) 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- 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- 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- 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- was competitively inhibited by pretreatment with PDGF-AA. We further demonstrate that HCMV glycoprotein B directly interacts with PDGFR-, resulting in receptor tyrosine phosphorylation, and that glycoprotein B neutralizing antibodies¹³ inhibit HCMV-induced PDGFR- phosphorylation. Taken together, these data indicate that PDGFR- is a critical receptor required for HCMV infection, and thus a target for novel anti-viral therapies.

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