Valganciclovir inhibits human adenovirus replication and pathology in permissive immunosuppressed female and male Syrian hamsters

• Published in: Viruses 2015-03, Vol.7 (3), p.1409-1428
• Main Authors: Toth, Karoly, Ying, Baoling, Tollefson, Ann E, Spencer, Jacqueline F, Balakrishnan, Lata, Sagartz, John E, Buller, Robert Mark L, Wold, William S M
• Format: Article
• Language: English
• Subjects: Adenovirus; Adenovirus Infections, Human - drug therapy; Adenovirus Infections, Human - pathology; Adenoviruses; Adenoviruses, Human - drug effects; Adenoviruses, Human - physiology; Animals; antiviral; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Case studies; Cell Line; Clinical trials; Cytomegalovirus; Disease Models, Animal; DNA polymerase; DNA-Directed DNA Polymerase - metabolism; Epithelial Cells - virology; Female; Ganciclovir - analogs & derivatives; Ganciclovir - pharmacology; Ganciclovir - therapeutic use; hamster; Human adenovirus; Humans; Immunocompromised Host; Infections; Kinases; Lipids; Liver - virology; Male; Mesocricetus; Pathology; Pediatrics; Stem cell transplantation; Survival Analysis; Treatment Outcome; valganciclovir; Viral Load; Virus Replication - drug effects; Viruses
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v7031409

Adenovirus infections of immunocompromised pediatric hematopoietic stem cell transplant patients can develop into serious and often deadly multi-organ disease. There are no drugs approved for adenovirus infections. Cidofovir (an analog of 2-deoxycytidine monophosphate) is used at times but it can be nephrotoxic and its efficacy has not been proven in clinical trials. Brincidofovir, a promising lipid-linked derivative of cidofovir, is in clinical trials. Ganciclovir, an analog of 2-deoxyguanosine, has been employed occasionally but with unknown efficacy in the clinic. In this study, we evaluated valganciclovir against disseminated adenovirus type 5 (Ad5) infection in our permissive immunosuppressed Syrian hamster model. We administered valganciclovir prophylactically, beginning 12 h pre-infection or therapeutically starting at Day 1, 2, 3, or 4 post-infection. Valganciclovir significantly increased survival, reduced viral replication in the liver, and mitigated the pathology associated with Ad5 infection. In cultured cells, valganciclovir inhibited Ad5 DNA replication and blocked the transition from early to late stage of infection. Valganciclovir directly inhibited Ad5 DNA polymerase in vitro, which may explain, at least in part, its mechanism of action. Ganciclovir and valganciclovir are approved to treat infections by certain herpesviruses. Our results support the use of valganciclovir to treat disseminated adenovirus infections in immunosuppressed patients.