Assessment of three antiviral compounds against Borealpox virus infection in a mouse model

Borealpox virus (BRPV) is a zoonotic orthopoxvirus which was first documented in Alaska in 2015. Although most human infections are mild, a recent fatal case in an immunocompromised individual highlights the importance of studying this emerging pathogen. To date, less then 10 human cases of BRPV infection have been confirmed which limits availability of clinical data on effectiveness of antiviral therapy. Here, we examined the effectiveness of cidofovir, brincidofovir and tecovirimat in cell culture and found all three were potent inhibitors of BRPV. In order to further study these modalities in vivo, we assessed immunocompetent and immunodeficient mice as disease models for BRPV. CAST/EiJ mice proved to be a suitable immunocompetent model for BRPV infection with high viral titers in several organs and route-dependent lethality. BRPV infection in immunodeficient mice, including STAT1-/-, scid, and NSG strains, was uniformly lethal and characterized by high viral titers as well as profuse fluid retention in the peritoneal cavity. Using CAST/EiJ mice, we then evaluated cidofovir, brincidofovir and tecovirimat therapy. Post-exposure treatment resulted in significant reductions in viral titers and an improved clinical course of infection. Our results demonstrate the utility of mouse models to study the pathogenicity of BRPV and support the use of these antivirals to treat human infections.Importance In humans, Borealpox virus (BRPV) is commonly associated with mild, self-limiting infections. However, in immunosuppressed individuals, infection can be severe and fatal. Due to a limited number of laboratory-confirmed cases and a lack of described animal models, little data on antiviral effectiveness against BRPV are available. Here we developed both immunocompetent and immunodeficient mouse models for the study of BRPV. In immunocompetent mice, BRPV infection resulted in high viral titers with organ-specific gross pathological abnormalities and route-dependant lethality. In immunodeficient mice, BRPV was uniformly lethal with varying times to lethal disease which appeared to coincide with viral replication. Notably, extensive fluid retention was also observed in these mice. Further assessment of cidofovir, brincidofovir, and tecovirimat therapy against BRPV infection demonstrated that all three compounds resulted in improved clinical condition and significant reductions in BRPV titers.