title: 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.affiliation: Saint Louis University School of Medicine, Department of Molecular Microbiology & Immunology, St. Louis, Missouri, USA.
authors.forename: Baoling
authors.initials: B
authors.lastname: Ying
authors.affiliation: Saint Louis University School of Medicine, Department of Molecular Microbiology & Immunology, St. Louis, Missouri, USA.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Tollefson
authors.affiliation: Saint Louis University School of Medicine, Department of Molecular Microbiology & Immunology, St. Louis, Missouri, USA.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Spencer
authors.affiliation: University of Rochester Medical Center, Department of Biochemistry and Biophysics, Rochester, New York, USA.
authors.forename: Lata
authors.initials: L
authors.lastname: Balakrishnan
authors.affiliation: University of Rochester Medical Center, Department of Microbiology & Immunology, Rochester, New York, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Dewhurst
authors.affiliation: The Ohio State University, Nationwide Childrens' Hospital, Columbus, Ohio, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Capella
authors.affiliation: Saint Louis University School of Medicine, Department of Molecular Microbiology & Immunology, St. Louis, Missouri, USA.
authors.forename: R Mark L
authors.initials: RM
authors.lastname: Buller
authors.affiliation: Saint Louis University School of Medicine, Department of Molecular Microbiology & Immunology, St. Louis, Missouri, USA toth@slu.edu.
authors.forename: Karoly
authors.initials: K
authors.lastname: Toth
authors.affiliation: Saint Louis University School of Medicine, Department of Molecular Microbiology & Immunology, St. Louis, Missouri, USA.
authors.forename: William S M
authors.initials: WS
authors.lastname: Wold
mesh_terms: D000257:Adenoviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000821:virology; D000260:Adenoviruses, Human / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008647:Mesocricetus; D063065:Organophosphonates / Q000494:pharmacology; D016019:Survival Analysis; D000637:Transaminases / Q000097:blood; D019562:Viral Load / Q000187:drug effects; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D014764:Viral Proteins; C525733:brincidofovir; D003596:Cytosine; D000637:Transaminases; D004259:DNA-Directed DNA Polymerase; D015774:Ganciclovir