Treatment of Lethal Vaccinia Virus Respiratory Infections in Mice with Cidofovir

Abstract

The interest in finding effective inhibitors of orthopoxviruses has increased due to the threat of either variola (smallpox) or monkeypox viruses in biowarfare or bioterrorism (Breman & Henderson, 1998;Hooper, 1998;Orent, 1998). Most members of the human population are susceptible to these viruses due to the discontinuation of the worldwide vaccination programme in the early 1980s. The viruses are likely candidates for biowarfare and bioterrorism because they are environmentally stable, easily propagated to high concentrations, and exhibit a high degree of infectivity by aerosol route.At the present time, no clinically approved treatment for smallpox, monkeypox or other orthopoxvirus infections exists. Of all the compounds tested over the years, only cidofovir (HPMPC) has emerged as being highly potent and efficacious. Cidofovir was shown to prevent mortality in cowpox virus infections Smee et al., 2000b) and to markedly delay the mean day of death (MDD) in vaccinia virus infections of severe combined immunodeficient (SCID) mice (Neyts & De Clercq, 1993). The drug was also found to be active in treating molluscum contagiosum in immunocompromised humans (Meadows et al., 1997). An unrelated drug, ribavirin, showed a more moderate degree of efficacy compared to cidofovir against cowpox virus infection ( Smee et al., 2000a). When combined with immune globulin, ribavirin effectively treated a progressive vaccinia virus infection in a human cancer patient (Kesson et al., 1997).Infection models in mice and rabbits have been used in the past to evaluate potential anti-poxvirus inhibitors. Probably the most commonly used mouse model has been intravenous inoculation of vaccinia virus into the tail vein, resulting in pox lesions on the tail (De Clercq et al., 1989). Neyts & De Clercq (1993) reported a lethal vaccinia virus infection in SCID mice for chemotherapy studies. Other, less commonly used vaccinia virus models include intracerebral inoculation of mouse brain (Schabel, 1968), infection of rabbit eyes (Sidwell et al., 1973), and infection of scarified rabbit skin (Sloan, 1975 Intranasal infection of BALB/c mice with the WR strain of vaccinia virus leads to pneumonia, profound weight loss and death. Five days after intranasal inoculation, virus from untreated mice was recovered from 11 organs, tissues and whole blood. The highest titres [>10 8 plaque forming units (pfu)/g] were in lungs and nose/sinus tissue, with about 10 7 pfu/g in spleen and blood. Seven other organs contained 30-to ≥50-fold lower amounts of virus. Mice infected with the related cowpox virus (for comparative purposes) had the majority of virus located in the respiratory tract. The vaccinia mouse model was used to study the efficacy of cidofovir treatments on the infection. Subcutaneous injections of 30 or 100 mg/kg/day, given on days 1 and 4 after virus challenge, reduced mortality by 60-100%. However, lung virus titres on days 2-5 were reduced no more than 10-fold by these treatments. A moderate improvement in drug efficacy occurred with daily tre...

Differential pathogenesis of cowpox virus intranasal infections in mice induced by low and high inoculum volumes and effects of cidofovir treatment

“…Less virus was produced in the spleen, liver, and brain in the 50-μl infection. Notably, barely detectable amounts of liver virus were seen during the course of the low volume infection, with only minimal levels present on day 8 of the of the higher volume infection, in contrast to the liver involvement reported with infections with other strains of cowpox and vaccinia viruses [4].…”

“…The virus strain that was used differs from the more typical cowpox virus [1,4] because it disseminated less to organs and tissues away from the lungs and/or sinus region following either a 5-μl or a 50-μl inoculum volume challenge. Particularly, there was minimal liver infection observed.…”

“…infection of mice with cowpox (Brighton strain) virus has been used as a small animal model to study treatments with antiviral agents [1,2]. Mice develop severe pneumonitis by this route of infection [3], and the virus disseminates to many organs and tissues [4]. Questions have been raised about the pathogenic factors that contribute to death of the animals, with three hypotheses proposed.…”

Development of Potent Orally Active Agents for Prevention and Treatment of Poxvirus Infection

“…Of particular interest was the finding that CDV and other phosphonate nucleotides were inhibitory to this group of viruses, including W, cowpox virus (CV), camelpox virus, monkeypox virus, and variola virus (J. W. Huggins, personal communication). The activity of CDV is of particular interest as a potential therapy for smallpox, as it is already approved for the treatment of cytomegalovirus (CMV) infections and has been shown to have activity in animal models using VV and CV (2,22,26,27). We have confirmed the activity of CDV against both VV and CV in tissue culture and animal models in our laboratory (4) inhibitors of orthopoxvirus replication in vitro and are highly effective in animal models when inoculated parenterally, they are absorbed poorly when given orally (1,5).…”

“…The best-known member of this class of compounds is CDV, which is currently approved for treatment of CMV infections in the immunocompromised host. This compound is a potent inhibitor of poxvirus replication in vitro (9) and has been shown to be very effective against both VV and CV infections in animal models, including in immunocompromised mice (2,4,22,26,27). Although there are other phosphonate nucleotides and their analogs, such as adefovir and adefovir dipivoxil, that are currently under evaluation in clinical studies for treatment of human immunodeficiency virus and/or hepatitis virus infections, there is far less information regarding their activity against poxvirus infections than is available for CDV (20).…”