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Alex Agelidis, James Hopkins, Deepak Shukla; Pharmacological inhibition of heparanase blocks release of HSV-1 from corneal epithelium. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3623.
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Little is known about the role of host factors in promoting HSV-1 infection. Additionally, the process of virus release from cells is not well characterized. Our study describes an important role for heparanase in egress of viral particles in a productive infection.
Several host cell types were employed in this study to examine the roles of heparanase in HSV-1 infection, including human corneal epithelial cells, corneal cultures of human and porcine origin, and murine corneas in vivo. Effects of a commercially available inhibitor of heparanase, OGT2115 (Tocris Bioscience), were studied in these infection models. Studies were performed with multiple HSV-1 strains including KOS, K26-GFP, beta-galactosidase-expressing KOS, McKrae, and 17syn+, and viral entry, replication, and release were measured by plaque assays, flow cytometry, quantitative PCR, western blot, and immunofluorescence microscopy. MTT assay was used to assess cell toxicity.
We found that prophylactic and therapeutic administration of OGT2115 resulted in significantly decreased virus released to the supernatant at multiple timepoints post infection, compared to DMSO. Early events during infection such as virus attachment, membrane translocation, fusion, and entry were not affected. We also found evidence for a connection of OGT2115 with modulation of autophagy. Dose titration and MTT assays showed low cell toxicity at the effective concentration.
Our study demonstrates that heparanase is an important host factor in release of virus from cells, and that this activity can be blocked by a chemical inhibitor. Given that heparan sulfate, the substrate of this enzyme, serves as an attachment receptor for multiple human viruses, it is possible that targeting heparanase could be an effective therapeutic strategy to reduce spread of infection.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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