Abstract
Herpes simplex virus (HSV) infections can be treated with direct acting antivirals like acyclovir and foscarnet, but long-term use can lead to drug resistance, which motivates research into broadly-acting antivirals that can provide a greater genetic barrier to resistance. Photodynamic inactivation (PDI) employs a photosensitizer, light, and oxygen to create a local burst of reactive oxygen species that inactivate microorganisms. The botanical plant extract OrthoquinTM is a powerful photosensitizer with antimicrobial properties. Here we report that Orthoquin also has antiviral properties. Photoactivated Orthoquin inhibited herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) infection of target cells in a dose-dependent manner across a broad range of sub-cytotoxic concentrations. HSV inactivation required direct contact between Orthoquin and the inoculum, whereas pre-treatment of target cells had no effect. Orthoquin did not cause appreciable damage to viral capsids or premature release of viral genomes, as measured by qPCR for the HSV-1 genome. By contrast, immunoblotting for HSV-1 antigens in purified virion preparations suggested that higher doses of Orthoquin had a physical impact on certain HSV-1 proteins that altered protein mobility or antigen detection. Orthoquin PDI also inhibited the non-enveloped adenovirus (AdV) in a dose-dependent manner, whereas Orthoquin-mediated inhibition of the enveloped vesicular stomatitis virus (VSV) was light-independent. Together, these findings suggest that the broad antiviral effects of Orthoquin-mediated PDI may stem from damage to viral attachment proteins.
Highlights
Herpes simplex viruses are ubiquitous and cause life-long infections of their human hosts
To confirm that the antiviral effect of Orthoquin was due to Photodynamic inactivation (PDI) effects on virions, plaque assays with three different Orthoquin treatments were performed; (i) Orthoquin was exposed to light before combining with Herpes simplex virus (HSV)-1 incolula, and infecting a HeLa monolayer; this treatment would allow us to determine whether Orthoquin antiviral activity was due to a photoproduct not acting through
PDI; (ii) Orthoquin was exposed to light before treating a HeLa cell monolayer with it for 1 h, rinsing it off and inoculating the cell monolayer with herpes simplex virus type 1 (HSV-1); this treatment would allow us to test whether a photoproduct of Orthoquin primes a light-independent antiviral response in cells before inoculation with HSV-1; or (iii) Orthoquin was mixed with HSV-1 and exposed to light, followed by infection of a HeLa monolayer
Summary
Herpes simplex viruses are ubiquitous and cause life-long infections of their human hosts. Abreva is incorporated into the cellular plasma membrane and prevents fusion steps essential for HSV-1 entry into epithelial cells [8] It must be applied repeatedly throughout the day due to rapid plasma membrane turnover and the subsequent loss of n-docosanol [9]. This host-targeted antiviral mechanism prevents development of viral resistance, but Abreva is only approved for perioral lesions, so there is a still a gap in treatment for lesions in other areas of the body. High doses of Orthoquin disrupted immunodetection of a subset of HSV-1 structural proteins by a pan-anti-HSV-1 polyclonal antibody, suggesting that PDI may cause physical damage to proteins on the virion exterior that prevents infection. We demonstrated light-dependent Orthoquin PDI of adenovirus infection and light-independent inhibition of vesicular stomatitis virus (VSV) infection
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