Ganciclovir inhibits human adenovirus replication and pathogenicity in permissive immunosuppressed Syrian hamsters.

Abstract

Adenovirus infections of immunocompromised patients can develop into deadly multiorgan or systemic disease. The virus is especially threatening for pediatric allogeneic hematopoietic stem cell transplant recipients; according to some studies, 10% or more of these patients succumb to disease resulting from adenovirus infection. At present, there is no drug approved for the treatment or prevention of adenovirus infections. Compounds that are approved to treat other virus infections are used off-label to combat adenovirus, but only anecdotal evidence of the efficacy of these drugs exists. Ganciclovir, a drug approved for the treatment of herpesvirus infection, was previously reported to be effective against human adenoviruses in vitro. To model adenovirus infections in immunocompromised humans, we examined ganciclovir's efficacy in immunosuppressed Syrian hamsters intravenously infected with type 5 human adenovirus (Ad5). This animal model is permissive for Ad5 replication, and the animals develop symptoms similar to those seen in humans. We demonstrate that ganciclovir suppresses Ad5 replication in the liver of infected hamsters and that it mitigates the consequences of Ad5 infections in these animals when administered prophylactically or therapeutically. We show that ganciclovir inhibits Ad5 DNA synthesis and late gene expression. The mechanism of action for the drug is not clear; preliminary data suggest that it exerts its antiadenoviral effect by directly inhibiting the adenoviral DNA polymerase. While more extensive studies are required, we believe that ganciclovir is a promising drug candidate to treat adenovirus infections. Brincidofovir, a drug with proven activity against Ad5, was used as a positive control in the prophylactic experiment.

• Authors: Baoling Ying, Ann E Tollefson, Jacqueline F Spencer, Lata Balakrishnan, Stephen Dewhurst, Cristina Capella, R Mark L Buller, Karoly Toth, William S M Wold
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 12 Pg. 7171-81 (Dec 2014) ISSN: 1098-6596 [Electronic] United States
• PMID: 25224011 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Chemical References

• Antiviral Agents
• Organophosphonates
• Viral Proteins
• brincidofovir
• Cytosine
• Transaminases
• DNA-Directed DNA Polymerase
• Ganciclovir

Topics

• Adenoviridae Infections (drug therapy, immunology, mortality, virology)
• Adenoviruses, Human (drug effects, genetics, growth & development, pathogenicity)
• Animals
• Antiviral Agents (pharmacology)
• Body Weight (drug effects)
• Cell Line, Tumor
• Cytosine (analogs & derivatives, pharmacology)
• DNA-Directed DNA Polymerase (genetics, metabolism)
• Female
• Ganciclovir (pharmacology)
• Gene Expression
• Humans
• Immunocompromised Host
• Male
• Mesocricetus
• Organophosphonates (pharmacology)
• Survival Analysis
• Transaminases (blood)
• Viral Load (drug effects)
• Viral Proteins (antagonists & inhibitors, genetics, metabolism)
• Virus Replication (drug effects)