Prophylactic treatment with BX795 blocks activation of AKT and its downstream targets to protect vaginal keratinocytes and vaginal epithelium from HSV-2 infection.

Genital herpes infections in humans are usually caused by herpes simplex virus type-2 (HSV-2), which result in recurrent lesions in the anogenital region. Past studies have shown that a viral protein translation inhibitor, BX795 is capable of mitigating HSV-2 infection both in vitro and in vivo when dosed therapeutically. However, any preventative benefits of this compound against HSV-2 infection remain poorly understood. In this study, we show that BX795 when added prophylactically to human vaginal keratinocytes generates strong preventative effects against a future HSV-2 infection. As a possible mechanism for this action, we found that BX795 efficiently reduces phosphorylation of AKT and its downstream targets p70S6K and 4EBP1. Our in-silico protein docking studies support our immunoblotting results and provide further credence to the proposed mechanism. Using a murine model of vaginal infection, we show that prior treatment with BX795 is also protective in vivo and leads to lower viral replication in the vaginal tissue. • BX795, a TBK1 inhibitor, shows new promise as a preventative antiviral against genital herpes infection. • Prophylactic treatment of vaginal keratinocytes with BX795 is non-toxic and shows sustained inhibition of HSV-2 replication. • Prophylactic antiviral effect of BX795 is also seen during HSV-2 entry into cells. • BX795 prophylactic treatment suppresses the AKT-p70S6K-4EBP1 pathway to suppress viral protein translation. • Pretreatment with BX795 is also safe and effective in a murine model of genital herpes infection. [ABSTRACT FROM AUTHOR]