Acriflavine as a Novel Venezuelan Equine Encephalitis Virus Therapeutic
Abstract
Venezuelan equine encephalitis virus (VEEV) is a positive-sense ssRNA virus whose transmission has increased in Central and South America with cases being reported in the southern United States. VEEV can infect humans in addition to equines and can cause encephalitis in both. There are no current FDA licensed vaccines or specific therapies against VEEV so development of novel therapeutic compounds is necessary to combat this new threat. With this aim, our research focuses on the possible interactions of VEEV with host microRNA (miRNA) machinery and how this pathway could prove to be a useful therapeutic target. Studies have shown that some viruses, like Hepatitis C virus, use the miRNA pathway to enhance replication. These interactions were tested through VEEV infection of cells deficient in selected miRNA processing machinery. In this study, we wanted to test the effects of some RISC inhibitors on VEEV replication. One of these inhibitors, acriflavine (ACF), is a derivative of acridine that is used as an antiseptic, fungicide and in the past was used to treat sleeping sickness. Treatment of VEEV infected cells with ACF dramatically reduced viral titers and protein expression when compared to controls. Intracellular capsid RNA levels were also reduced in ACF treated cells. Differentiated neurons infected with VEEV also showed increased survival and had lower viral titers upon treatment with ACF. When tested on a murine model, ACF increased survival in C3H/HeN mice compared to the placebo. Combined, these results suggest miRNA genesis is necessary for productive VEEV infection, with the nuclear processing and RISC-binding steps being most significant and that ACF could serve as an effective therapeutic for VEEV infection.
Description
Keywords
Acriflavine, VEEV, MiRNA, Therapeutic, Argonoute 2