Gaudichaudione H inhibits Herpes Simplex Virus-1 replication by regulating cellular nuclear factor-κB in an interferon-γ-independent manner

Abstract

The highly prevalent herpes simplex virus type 1 (HSV-1) causes keratoconjunctivitis and encephalitis. Viral DNA polymerase-inhibiting nucleoside analogs (such as acyclovir) are standard treatment agents against HSV infections but are limited by severe drug resistance issues. Thus, new antiviral agents with novel targets are urgently needed. Earlier, we investigated the anti-cancer, anti-inflammatory, and antibacterial bioactivities of Garcinia sp. Here, we report that non-cytotoxic concentrations (< 500 nM) of Gaudichaudione H (GH, isolated from Garcinia oligantha Merr.) potently inhibits HSV-1 replication in vitro without affecting viral entry or attachment. GH inhibits the expression of the viral proteins ICP0, ICP4, and ICP27 without affecting their mRNA levels. In Vero cells, GH enhanced STAT1 and 3 phosphorylation, which occurs downstream to interferon (IFN)-{gamma} activation during viral infections. However, pharmacological/genetic inhibition of IFN-{gamma} failed to suppress the GH-mediated inhibition of HSV-1 replication, indicating that GH exerts antiviral effects independent of IFN. Further mechanistic studies suggest that GH inhibits HSV-1 replication, at least partially by inhibiting cellular NF-{kappa}B activation. Moreover, GH prolonged the survival rate of KOS-infected mice by 25% (n = 5). In conclusion, GH treatment inhibits HSV-1 replication both in vitro and in vivo; therefore, it can be developed as an antiviral. ImportanceVery few therapeutic drug options are available to treat herpes simplex virus-1/2 which cause myriad debilitating diseases. We screened eight Garcinia compounds and found Gaudichaudione H was the most effective compound at non-cytotoxic concentrations. Further mechanism study illustrates that GH inhibits HSV-1 replication, at least partially by inhibiting cellular NF-{kappa}B activation. Natural compound is a promising resource of new antiviral agents with different targets that has ability to treat resistant viral strains.