Abstract
Cell-free human cytomegalovirus (HCMV) can be inhibited by a soluble form of the cellular HCMV-receptor PDGFRα, resembling neutralization by antibodies. The cell-associated growth of recent HCMV isolates, however, is resistant against antibodies. We investigated whether PDGFRα-derivatives can inhibit this transmission mode. A protein containing the extracellular PDGFRα-domain and 40-mer peptides derived therefrom were tested regarding the inhibition of the cell-associated HCMV strain Merlin-pAL1502, hits were validated with recent isolates, and the most effective peptide was modified to increase its potency. The modified peptide was further analyzed regarding its mode of action on the virion level. While full-length PDGFRα failed to inhibit HCMV isolates, three peptides significantly reduced virus growth. A 30-mer version of the lead peptide (GD30) proved even more effective against the cell-free virus, and this effect was HCMV-specific and depended on the viral glycoprotein O. In cell-associated spread, GD30 reduced both the number of transferred particles and their penetration. This effect was reversible after peptide removal, which allowed the synchronized analysis of particle transfer, showing that two virions per hour were transferred to neighboring cells and one virion was sufficient for infection. In conclusion, PDGFRα-derived peptides are novel inhibitors of the cell-associated spread of HCMV and facilitate the investigation of this transmission mode.
Highlights
The entry of human cytomegalovirus (HCMV) can be inhibited by a soluble derivative of its entry receptor platelet-derived growth factor receptor alpha (PDGFRα) [17,18,19], which acts as a decoy receptor by binding to the viral glycoprotein O. gO is a component of the trimeric envelope complex that mediates entry into fibroblasts [20,21,22]
PDGFRα-Fc inhibits cell-free infection of HCMV by acting as a decoy receptor that binds to the viral envelope protein gO [17,18,19], whereas its effect on cell-associated spread has not been conclusively elucidated
The findings obtained with laboratory strain TB40 suggest that this decoy receptor cannot inhibit cell-associated spread of HCMV, as it did not reduce focal size more than an overlay medium or neutralizing antibodies [19], treatments that are assumed to block cell-free virus transmission
Summary
PDGFRα-domain and 40-mer peptides derived therefrom were tested regarding the inhibition of the cell-associated HCMV strain Merlin-pAL1502, hits were validated with recent isolates, and the most effective peptide was modified to increase its potency. PDGFRα-derived peptides are novel inhibitors of the cell-associated spread of HCMV and facilitate the investigation of this transmission mode. Ganciclovir, valganciclovir and cidofovir, several antiviral drugs targeting the viral polymerase are available for treatment or prevention of HCMV-associated disease. Their use is, associated with toxic side effects and emergence of resistance, limiting their application in certain situations [4,5].
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