Abstract
Adenovirus infections of immunocompromised patients can cause a severe multi-organ disease that often results in the patients’ death. Presently, there are no drugs specifically approved to treat adenovirus infections, and clinicians resort to the off-label use of antivirals that are approved to treat other DNA virus infections, most frequently cidofovir (CDV). CDV, however, has considerable nephrotoxicity, thus it is recommended only for the most severe cases of adenovirus infections. To facilitate the development of effective, non-toxic antivirals against adenovirus, we have developed a permissive animal model based on the Syrian hamster that can be used to test the efficacy of antiviral compounds. Here, we show that in the hamster model, HAdV-C6 is a more useful challenge virus than the previously described HAdV-C5, because it is filtered out by tissue macrophages to a lesser extent. HAdV-C6 has a 10-fold lower LD50 in hamsters than HAdV-C5 and the pathology is caused by virus replication to a larger extent. We show that valganciclovir (VGCV), a drug that was shown to be active against intravenous HAdV-C5 infection previously, is efficacious against HAdV-C6 when administered either prophylactically or therapeutically. Further, we show for the first time that VGCV, and to a lesser extent CDV, can be used to treat respiratory adenovirus infections in the hamster model. These results extend the utility of the hamster model, and demonstrate the efficacy of two drugs available for clinicians to treat adenovirus infections.
Highlights
Adenoviruses (Ads) are viruses with a non-enveloped icosahedral capsid and a double-strandedDNA genome
We developed an animal model based on the permissive Syrian hamsters, which is amenable for in vivo studies to test the efficacy of anti-adenoviral compounds [24,25,26,27]
Consistent with this hypothesis, VGCV treatment of hamsters challenged intranasally with Ad6 significantly decreased body weight loss, inhibited the replication of Ad6 in the lungs, and mitigated the pathogenic effects of Ad6. This is the first time that we showed that an antiviral drug inhibits the replication of a human Ad in the lungs of immunosuppressed hamsters, and that this inhibition results in decreased morbidity
Summary
Adenoviruses (Ads) are viruses with a non-enveloped icosahedral capsid and a double-stranded. Ads is endemic among military recruits, causing severe acute respiratory disease (for Ad pathology, see [3,5,6]). It is immunocompromised patients who suffer the most severe consequences. The defective immune systems of these patients cannot eliminate the virus, and the infection can lead to a serious, often life-threatening multi-organ illness. The replication of the virus will lead to high virus burden and hepatocellular necrosis, and the animals will present with quantifiable pathology (mortality, body weight loss, elevation of serum transaminase levels, microscopic pathology) [30,31], to immunocompromised patients with advanced disseminated multi-organ Ad infections. We show that a drug is effective against respiratory challenge with Ad
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