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The host enzyme heparanase (HPSE) facilitates the release of herpes simplex virus type 2 (HSV-2) from target cells by cleaving the viral attachment receptor heparan sulfate (HS) from infected cell surfaces. HPSE 2, an isoform of HPSE, binds to but does not possess the enzymatic activity needed to cleave cell surface HS. Our study demonstrates that HSV-2 infection significantly elevates HPSE 2 protein levels, impacting two distinct stages of viral replication. We show that higher HPSE 2 negatively affects HSV-2 replication which may be through the regulation of cell surface HS. By acting as a competitive inhibitor of HPSE, HPSE 2 may be interfering with HPSE's interactions with HS. We demonstrate that the enhanced expression of HPSE 2, either via viral infection or plasmid transfection, reduces HPSE's ability to cleave HS, thereby hindering viral egress. Conversely, low HPSE 2 levels achieved through siRNA transfection allow HPSE to cleave more HS, reducing viral entry. Altogether, we propose a hypothetical model in which the modulation of HPSE 2 impedes HSV-2 replication by regulating HS availability on the cell surface. This dual role of HPSE 2 in viral replication and potential tumor suppression underscores its significance in cellular processes and viral pathogenesis. [ABSTRACT FROM AUTHOR]

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]