| Abstrakt: |
Murine gammaherpesvirus 68 (MHV-68) is a rodent virus related to human Epstein—Barr virus (EBV). MHV-68 infection and its treatment were studied in a novel lethal immunosuppression model in BALB/c mice. Intranasally infected mice that were immunosuppressed with cyclophosphamide developed persistently high virus titres in pulmonary tissue, and to a lesser extent, in splenic tissue. These animals died from infection within 12 days, whereas normal mice resolved the infection by day 10 and survived. Cyclophosphamide-treated infected mice had significant decreases in natural killer cell activity, T and B cell proliferative responses, and T and B cell numbers compared to immunocompetent uninfected and infected animals. In order to study the treatment of the lethal infection, 16 known inhibitors of EBV or other herpesviruses were first evaluated against MHV-68 by plaque reduction assay in African green monkey kidney (MA-104) cells. Of these compounds, fialuridine (FIAU) had the most potent effect, inhibiting 50% of viral plaques at 0.1 μM. By comparison, cidofovir (HPMPC), HPMPA, acyclovir and ganciclovir were inhibitory at 1.2, 0.9, 6.7 and 10 μM respectively. Cyclophosphamide-immunosuppressed infected mice were treated intraperitoneally with acyclovir, FIAU, HPMPC or placebo for 5 days starting 24 h after virus challenge. Acyclovir treatment (70 mg kg-1 day-1) did not increase survival time significantly but decreased lung virus titres sixfold as measured on day 9 of the infection; FIAU treatments (5 mg kg-1 day-1) caused a 2.4 day delay in death and reduced lung virus titres greater than 15-fold. HPMPC treatments (5 mg kg-1 day-1) resulted in a 13 day delay in death, and reduced virus production in the lung over 3000-fold compared with the placebo group. HPMPC appears to be an excellent candidate for treating EBV virus infections in humans, particularly in immunocompromised patients in whom infections may be life-threatening. |
