Key result
Treatment with cidofovir or S-2242 at 100 mg/kg significantly delayed MAV-1-related death in SCID mice, although it did not completely suppress virus replication.
Why the study?
Does cidofovir or S-2242 delay MAV-1-related death in SCID mice infected with MAV-1?
Does cidofovir or S-2242 delay MAV-1-related death in SCID mice infected with MAV-1?
The MAV-1/SCID mouse model is an appropriate in vivo model for evaluating antiadenovirus agents, demonstrating that cidofovir and S-2242 delay mortality but do not achieve complete viral clearance without an adaptive immune response.
Supports MAV-1/SCID model for anti-adenovirus testing; leaves open human translation without adaptive immunity.
The importance of human adenovirus infections in immunocompromised patients urges for new and adequate antiadenovirus compounds. Since human adenoviruses are species specific, animal models for systemic adenovirus infections rely on a nonhuman adenovirus. We established mouse adenovirus type 1 (MAV-1) infection of BALB/c SCID mice as a model for the evaluation of antiadenovirus therapy. In vitro studies with mouse embryonic fibroblasts pointed to the acyclic nucleoside phosphonate cidofovir and the N-7-substituted acyclic derivative 2-amino-7-(1,3-dihydroxy-2-propoxymethyl)purine (S-2242) as markedly active compounds against MAV-1. SCID mice, infected intranasally with MAV-1, developed a fatal disseminated infection after approximately 19 days, characterized by hemorrhagic enteritis. Several techniques were optimized to monitor viral, immunological, and pathological aspects of MAV-1 infection. Real-time PCR quantification of viral DNA revealed that after replication in the lungs, virus disseminated to several organs, including the brain, liver, spleen, intestine, heart, and kidneys (resulting in viruria). Immunohistochemical staining showed that MAV-1 was localized in the endothelial cells of the affected organs. Using reverse transcription-PCR, tissue levels of proinflammatory cytokines (i.e., interleukin-1beta and tumor necrosis factor alpha) were found to be markedly increased. The MAV-1/SCID model appears to be an appropriate model for in vivo evaluation of antiadenovirus agents. Treatment with cidofovir or S-2242 at a dose of 100 mg per kg of body weight resulted in a significant delay in MAV-1-related death, although these antivirals were unable to completely suppress virus replication despite continued drug treatment. These findings suggest that complete virus clearance during antiviral therapy for disseminated adenovirus infection may require an efficient adaptive immune response from the host.
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Lenaerts et al. (2005) studied Systemic adenovirus infection. Cidofovir or S-2242 was evaluated on MAV-1-related death. Treatment with cidofovir or S-2242 at 100 mg/kg significantly delayed MAV-1-related death in SCID mice, although it did not completely suppress virus replication.
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