title: Buccal viral DNA as a trigger for brincidofovir therapy in the mousepox model of smallpox.
abstract: Orthopoxviruses continue to pose a significant threat to the population as potential agents of bioterrorism. An intentional release of natural or engineered variola virus (VARV) or monkeypox viruses would cause mortality and morbidity in the target population. To address this, antivirals have been developed and evaluated in animal models of smallpox and monkeypox. One such antiviral, brincidofovir (BCV, previously CMX001), has demonstrated high levels of efficacy against orthopoxviruses in animal models and is currently under clinical evaluation for prevention and treatment of diseases caused by cytomegaloviruses and adenoviruses. In this study we use the mousepox model of smallpox to evaluate the relationship between the magnitude of the infectious virus dose and an efficacious BCV therapy outcome when treatment is initiated concomitant with detection of ectromelia virus viral DNA (vDNA) in mouse buccal swabs. We found that vDNA could be detected in buccal swabs of some, but not all infected mice over a range of challenge doses by day 3 or 4 postexposure, when initiation of BCV treatment was efficacious, suggesting that detection of vDNA in buccal swabs could be used as a trigger to initiate BCV treatment of an entire potentially exposed population. However, buccal swabs of some mice did not become positive until 5 days postexposure, when initiation of BCV therapy failed to protect mice that received high doses of virus. And finally, the data suggest that the therapeutic window for efficacious BCV treatment decreases as the virus infectious dose increases. Extrapolating these findings to VARV, the data suggest that treatment should be initiated as soon as possible after exposure and not rely on a diagnostic tool such as the measurement of vDNA in buccal cavity swabs; however, consideration should be given to the fact that the behavior/disease-course of VARV in humans is different from that of ectromelia virus in the mouse.
authors.affiliation: Saint Louis University School of Medicine, 1100 S. Grand Blvd, St. Louis, MO 63104, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Crump
authors.affiliation: The George Washington University, School of Medicine and Health Sciences, Department of Microbiology, Immunology and Tropical Medicine, 2300 Eye Street, NW Washington, DC 20037, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Korom
authors.affiliation: Saint Louis University School of Medicine, 1100 S. Grand Blvd, St. Louis, MO 63104, USA.
authors.forename: R Mark
authors.initials: RM
authors.lastname: Buller
authors.affiliation: Saint Louis University School of Medicine, 1100 S. Grand Blvd, St. Louis, MO 63104, USA. Electronic address: scott9379@gmail.com.
authors.forename: Scott
authors.initials: S
authors.lastname: Parker
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004279:DNA, Viral / Q000187:drug effects* / Q000302:isolation & purification; D004195:Disease Models, Animal; D004481:Ectromelia virus / Q000187:drug effects*; D004482:Ectromelia, Infectious / Q000188:drug therapy* / Q000821:virology; D051379:Mice; D009061:Mouth Mucosa / Q000821:virology*; D063065:Organophosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D018155:Orthopoxvirus / Q000187:drug effects; D012899:Smallpox / Q000188:drug therapy / Q000821:virology
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; C525733:brincidofovir; D003596:Cytosine
keywords: Antiviral; Brincidofovir; CMX001; Ectromelia; Variola virus; Viral DNA