Date Published: April 12, 2017
Publisher: Public Library of Science
Author(s): Yiquan Wu, Adrian Prager, Simone Boos, Moritz Resch, Ilija Brizic, Michael Mach, Sabrina Wildner, Laura Scrivano, Barbara Adler, Andrew Yurochko.
Herpesvirus gH/gL envelope glycoprotein complexes are key players in virus entry as ligands for host cell receptors and by promoting fusion of viral envelopes with cellular membranes. Human cytomegalovirus (HCMV) has two alternative gH/gL complexes, gH/gL/gO and gH/gL/UL128,130,131A which both shape the HCMV tropism. By studying binding of HCMV particles to fibroblasts, we could for the first time show that virion gH/gL/gO binds to platelet-derived growth factor-α (PDGFR-α) on the surface of fibroblasts and that gH/gL/gO either directly or indirectly recruits gB to this complex. PDGFR-α functions as an entry receptor for HCMV expressing gH/gL/gO, but not for HCMV mutants lacking the gH/gL/gO complex. PDGFR-α-dependent entry is not dependent on activation of PDGFR-α. We could also show that the gH/gL/gO—PDGFR-α interaction starts the predominant entry pathway for infection of fibroblasts with free virus. Cell-associated virus spread is either driven by gH/gL/gO interacting with PDGFR-α or by the gH/gL/UL128,130,131A complex. PDGFR-α-positive cells may thus be preferred first target cells for infections with free virus which might have implications for the design of future HCMV vaccines or anti-HCMV drugs.
Human cytomegalovirus (HCMV) is a human herpesvirus which is spread worldwide and can cause life-threatening infections in immunocompromised patients. Additionally, it is one of the major causes of virus-induced birth defects after congenital infection. Like all herpesviruses, it persists lifelong in its host. HCMV disease in immunocompromised patients and intrauterine infection with HCMV can be observed both after primary infection and after reactivation . One hallmark of HCMV infection is the broad cell tropism observed in vivo , which is shaped by a number of different envelope glycoprotein complexes.
Expression of PDGFR-α is important for infection of cells with HCMV. Knockdown of PDGFR-α, soluble PDGFR-α, anti-PDGFR-α antibodies or PDGF-AA all strongly inhibit HCMV infection and re-introduction of PDGFR-α in knockout cells reconstitutes infection [23,32]. Using recombinant HCMV gB, binding of gB to PDGFR-α has been shown [23,42]. Similarly, recombinant gH/gL/gO complex has been used to precipitate PDGFR-α from cell lysates . In the latter study, a PDGFR-α—gH/gL/gO complex with PDGFR-α directly interacting with gO could be visualized by electron microscopy. Additionally, all three studies proposed an enhancement of infection by activation of PDGFR-α [23,32,42]. Thus, PDGFR-α as an entry receptor for HCMV recognized by gB and/or gH/gL/gO and PDGFR-α as a signaling ligand for HCMV are two concepts which require confirmation or disproof.