Topical Treatment of Cutaneous Vaccinia Virus Infections in Immunosuppressed Hairless Mice with Selected Antiviral Substances

Abstract

Background: Certain nucleoside, nucleotide and pyrophosphate analogues may be useful for treating severe complications arising as a result of virus dissemination following smallpox (live vaccinia virus) vaccinations, especially in immunocompromised individuals. We used an immunosuppressed hairless mouse model to study the effects of 10 antiviral agents on progressive vaccinia infections. Methods: Hairless mice were immunosuppressed by treatment with cyclophosphamide (100 mg/kg) every 4 days starting 1 day prior to vaccinia virus (WR strain) infection of wounded skin. Topical treatments with antiviral agents were applied twice a day for 7 days starting 5 days after virus exposure. Results: Topical 1% cidofovir cream treatment was effective in significantly reducing primary lesion severity and decreasing the number of satellite lesions. Topical 1% cyclic HPMPC and 1% phosphonoacetic acid were not quite as active as cidofovir. Ribavirin (5%) treatment reduced lesion severity and diminished the numbers of satellite lesions, but the mice died significantly sooner than placebos. 2-Amino-7-[(1,3,-dihydroxy-2-propoxy)methyl]purine (compound S2242; 1%) moderately reduced primary lesion sizes. Ineffective treatments included 5% arabinosyladenine, 1% arabinosylcytosine, 1% 5-chloro-arabinosylcytosine, 5% arabinosylhypoxanthine 5-monophosphate and 5% viramidine. Conclusions: Of the compounds tested, topically applied cidofovir was the most effective treatment of cutaneous vaccinia virus infections in immunosuppressed mice. Topical treatment with cidofovir could be considered as an adjunct to intravenous drug therapy for serious infections.

Mutations Conferring Resistance to Viral DNA Polymerase Inhibitors in Camelpox Virus Give Different Drug-Susceptibility Profiles in Vaccinia Virus

“…Other studies presented similar observations with genotypically characterized HPMPC R and HPMPDAP R VACV and demonstrated the antiviral efficacies of (S)-HPMPC, (S)-HPMP-5-azaC and CMX001 (4,32,43). Recently, a PAA-based cream therapy reduced primary lesion area and delayed the mortality of immunosuppressed mice infected cutaneously with VACV-WR (58). Therefore, it might be valuable to investigate the inhibitory effect of PAA against HPMPDAP R and HPMPC R VACV or CMLV since such viruses exhibited hypersensitivity to this molecule.…”

Orthopoxvirus targets for the development of new antiviral agents

“…Inhibitors that disrupt the interaction between D4R and A20R have also been identified and have been reported to inhibit viral replication (Schormann et al, 2011). Phosphonoacetic acid was also shown to be effective in an animal model of vaccinia virus infection and presumable inhibits the DNA polymerase directly (Smee et al, 2011). …”

Cutaneous Deficiency of Filaggrin and STAT3 Exacerbates Vaccinia Disease In Vivo

“…Studies of ACAM-2000 infection in FT mice have not been previously published. To extend our evaluation of anti-vaccinia to FT mice, which are euthymic, we adapted a published vaccinia scarification model in immunosuppressed hairless mice [8] (Fig 1). Briefly, FT mice pretreated with the immunosuppressant cyclophosphamide (Cytoxan, CTX) and topical STAT3 inhibitor or vehicle were scarified with ACAM-2000 (10 6 pfu), applied with a bifurcated needle in two locations 2 mm apart on the shaved back of mice.…”

“…Cyclophosphamide (Santa Cruz Biotech, Dallas, TX) was administered by intraperitoneal route starting with the day prior to vaccinia scarification and every 4 days after vaccinia infection as previously described [8]. Scarification using 10 6 pfu ACAM-2000 was performed as previously described [4].…”