Research Article: A derivative of platelet-derived growth factor receptor alpha binds to the trimer of human cytomegalovirus and inhibits entry into fibroblasts and endothelial cells

Date Published: April 12, 2017

Publisher: Public Library of Science

Author(s): Cora Stegmann, Daniel Hochdorfer, Diana Lieber, Narmadha Subramanian, Dagmar Stöhr, Kerstin Laib Sampaio, Christian Sinzger, Andrew Yurochko.

http://doi.org/10.1371/journal.ppat.1006273

Abstract

Human cytomegalovirus (HCMV) is a widely distributed herpesvirus that causes significant morbidity in immunocompromised hosts. Inhibitors of viral DNA replication are available, but adverse effects limit their use. Alternative antiviral strategies may include inhibition of entry. We show that soluble derivatives of the platelet-derived growth factor receptor alpha (PDGFR-alpha), a putative receptor of HCMV, can inhibit HCMV infection of various cell types. A PDGFR-alpha-Fc fusion protein binds to and neutralizes cell-free virus particles at an EC50 of 10–30 ng/ml. Treatment of particles reduced both attachment to and fusion with cells. In line with the latter, PDGFR-alpha-Fc was also effective when applied postattachment. A peptide scan of the extracellular domain of PDGFR-alpha identified a 40mer peptide that inhibits infection at an EC50 of 1–2 nmol/ml. Both, peptide and fusion protein, were effective against various HCMV strains and are hence promising candidates for the development of novel anti-HCMV therapies.

Partial Text

Human cytomegalovirus (HCMV) is a pathogenic human beta-herpesvirus that shares the property of other beta-herpesviruses to replicate only in its specific host. Primary infection is followed by lifelong latent persistence with occasional reactivation of the virus, which usually goes unnoticed by the infected individual. However, under conditions of insufficient immune responses, HCMV can cause severe or even life-threatening disease, e.g. in AIDS patients, transplant recipients, and fetuses infected in utero. Although antiviral drugs are available, their use is limited due to associated adverse effects and the development of resistance [1, 2]. Therefore, alternative treatment options are desired.

The finding that soluble platelet-derived growth factor receptor alpha binds to HCMV virions only if they contain the gH/gL/gO trimer, thereby inhibiting entry into fibroblasts and endothelial cells, has implications for our basic understanding of HCMV entry and may provide the starting point for a novel antiviral strategy.

 

Source:

http://doi.org/10.1371/journal.ppat.1006273

 

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