Effects of cidofovir on the pathogenesis of a lethal vaccinia virus respiratory infection in mice

Abstract

Intranasal infection of BALB/c mice with the WR strain of vaccinia virus leads to pneumonia, profound weight loss, and death. Although the major sites of virus replication are in the lungs and nasal tissue, dissemination of the virus to other visceral organs and brain occurs via the blood. In this report the effects of cidofovir on the pathogenesis of the infection was studied. Mice were infected intranasally with virus followed 1 day later by a single intraperitoneal treatment with cidofovir (100 mg/kg) or placebo. Placebo-treated mice were dead by day 8, whereas all cidofovir-treated animals survived through 21 days. Cidofovir treatment did not prevent profound weight loss from occurring during the acute phase of the infection, but the mice gained weight quickly after the 8th day. Significantly higher arterial oxygen saturation levels, as determined by pulse oximetry, were seen in cidofovir-treated animals compared to placebos on days 4–7. Cidofovir treatment markedly improved lung consolidation scores and prevented lung weights from increasing during the infection. Virus titers in lungs and nasal tissue were high starting from the first day of the infection, whereas the titers in liver, spleen, brain, and blood was low for 3 days then markedly rose between days 4 and 6. Lung and nasal virus titers were reduced 10–30-fold by cidofovir treatment on days 2, 4 and 6. Virus titers in the other tissues and blood at their peak (day 6) were 30- to >1000-fold less than in tissues of placebos. These results illustrate the ability of a single cidofovir treatment to control the pathogenesis of an acute lethal infection in various tissues during the vaccinia virus infection in mice.