RAT CYTOMEGALOVIRUS-INDUCED PNEUMONITIS AFTER ALLOGENEIC BONE-MARROW TRANSPLANTATION - EFFECTIVE TREATMENT WITH (S)-1-(3-HYDROXY-2-PHOSPHONYL-METHOXYPROPYL)CYTOSINE

Two antiviral compounds, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) and 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), were evaluated for their effects on rat cytomegalovirus (RCMV)-induced interstitial pneumonitis after allogeneic bone marrow transplantation (BMTx). Eight-week-old Brown Norway rats immunosuppressed by a lethal dose of total body irradiation were inoculated with RCMV and received allogeneic bone marrow cells from Lewis rats. Animals were treated with either HPMPC (20 mg/kg of body weight as a single dose) or DHPG (20 mg/kg as two daily doses for 5 days). The effect of antiviral therapy was monitored by measuring RCMV titers in different organs and the histopathologic changes in lungs at 8 to 10 days postinfection. In RCMV-infected allogeneic BMTx recipients, severe diffuse thickening of alveolar septa (6.02 mum) with a diffuse infiltration of mononuclear cells occurred, whereas in the noninfected allogeneic BMTx recipients, the septal width was on the order of 2 mum (P < 0.01). Treatment with DHPG (20 mg/kg in two daily doses for 5 days) resulted in a decrease in virus titers (log10 PFU per gram of tissue) in lungs and spleens from 3.81 +/- 0.34 and 4.29 +/- 1.07 (untreated animals) to 1.26 +/- 0.53 and 3.22 +/- 0.27 (treated animals), respectively. Treatment with HPMPC (20 mg/kg as a single dose) resulted in a complete reduction of virus titers in all organs to below the detection level (P < 0.01). Furthermore, antiviral treatment resulted in a reduction of the alveolar septal width from 6.02 +/- 1.59 mum (untreated animals) to 4.67 +/- 1.70 and 3.32 +/- 0.63 mum after DHPG and HPMPC treatment, respectively. Furthermore, the influx of mononuclear cells in the alveolar septa was significantly impaired after treatment with HPMPC (P < 0.01). We conclude that in the described rat model, HPMPC is highly effective in suppressing RCMV-induced interstitial pneumonitis after allogeneic BMTx.