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

Karoly Toth,Ann Tollefson,John Sagartz,Jacqueline Spencer,Baoling Ying,Lata Balakrishnan,Robert Buller,William Wold

doi:10.3390/v7031409

Abstract

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.

Highlights

There are close to 70 types of human adenoviruses (Ads) described in the literature, named Ad1, Ad2, etc., that form seven species (A–G)
In order to determine whether VGCV is active against adenovirus type 5 (Ad5) challenge when applied therapeutically, we used the highest dose from the MTD experiment (200 mg/kg twice daily (b.i.d.)
We have employed the permissive immunosuppressed Syrian hamster model to study the ability of VGCV to inhibit Ad5 replication in the liver and Ad5-induced pathology

Summary

Introduction

There are close to 70 types of human adenoviruses (Ads) described in the literature, named Ad1, Ad2, etc., that form seven species (A–G). There are no drugs approved to treat Ad infections, i.e., no controlled clinical trials have been completed leading to approval of any anti-Ad drug. Cidofovir (CDV), an acyclic nucleoside phosphonate analog of 2-deoxycytidine monophosphate, is often used in the clinic for immunosuppressed pediatric allogeneic hematopoietic stem cell transplant patients with rising titers of Ad in the blood as determined by quantitative polymerase chain reaction (qPCR) [1,3,4,5]. CDV (a monophosphate) is phosphorylated to the diphosphate form by cellular kinases; the diphosphate form is used as a substrate by the viral DNA polymerase, leading to incorporation of CDV and, eventually, to chain termination [6]. The specificity of CDV for many DNA viruses comes from the higher affinity of the viral enzymes for CDV-diphosphate.

Methods

Results

Conclusion