Ganciclovir Treatment of Murine Cytomegalovirus Infection in Mice Immunosuppressed by Prior Infection With Friend Leukaemia Virus

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Antiviral Chemistry & Chemotherapy



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Since many of the severe cytomegalovirus infections in humans occur in individuals immunosuppressed by the human immunodeficiency virus, we developed an analogous murine model for studying this disease. BALB/c mice infected with the Friend retrovirus complex (FV) were immunosuppressed (i.e., exhibited reduced spleen-cell mitogenic responses and natural killer cell activity) by 21 days after FV inoculation. Challenge with murine cytomegalovirus (MCMV) at that time led to mortality at doses generally non-lethal to normal mice. Superinfection of FV-infected mice with MCMV reduced spleen cell FV infectious centres and splenomegaly, and extended the lives of mice surviving the MCMV infection. Once-daily ganciclovir treatments of 12.5,25, and 50 mg kg−1 given to dually-infected mice for 5 days starting 24 h after MCMV inoculation resulted in 90–100% survival at 14 days (relative to MCMV inoculation) compared to 15% survival in the placebo group. By 70 days, survival in the drug-treated and placebo groups were 0–5%, these deaths being attributed to FV disease. Ganciclovir treatments reduced MCMV titres in spleen, liver, and kidney during treatment (day 4 of the infection), but lung and salivary gland titres rose between days 7 and 13 in surviving animals. Improved concanavalin A-induced mitogenic responses were noted on day 4 in mice treated with 25 and 50 mg kg−1. These results indicate that the FV/MCMV dual infection in mice can be used as a model for evaluating antiviral agents. Because of the complex nature of the interaction between FV and MCMV, the model may be more appropriate for advanced studies of well-defined viral inhibitors than for routine screening of potential new compounds.