title: Inhibition of adenovirus infections by siRNA-mediated silencing of early and late adenoviral gene functions.
abstract: Adenoviruses are pathological agents inducing mild respiratory and gastrointestinal infections. Under certain circumstances, for example in immunosuppressed patients, they induce severe infections of the liver, heart and lung, sometimes leading to death. Currently, adenoviral infections are treated by palliative care with no curative antiviral therapy yet available. Gene silencing by RNA interference (RNAi) has been shown to be a potent new therapeutic option for antiviral therapy. In the present study, we examined the potential of RNAi-mediated inhibition of adenovirus 5 infection by the use of small interfering (si)RNAs targeting both early (E1A) and late (hexon, IVa2) adenoviral genes. Several of the initially analyzed siRNAs directed against E1A, hexon and IVa2 showed a distinct antiviral activity. Among them, one siRNA for each gene was selected and used for the further comparative investigations of their efficiency to silence adenoviruses. Silencing of the late genes was more efficient in inhibiting adenoviral replication than comparable silencing of the E1A early gene. A combination strategy involving down-regulation of any two or all three of the targeted genes did not result in an enhanced inhibition of viral replication as compared to the single siRNA approaches targeting the late genes. However, protection against adenovirus-mediated cytotoxicity was substantially improved by combining siRNAs against either of the two late genes with the siRNA against the E1A early gene. Thus, an enhanced anti-adenoviral efficiency of RNAi-based inhibition strategies can be achieved by co-silencing of early and late adenoviral genes, with down regulation of the E1A as a crucial factor.
authors: Department of Cardiology & Pneumology, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors: Anne
authors: A
authors: Eckstein
authors: Tobias
authors: T
authors: Grössl
authors: Anja
authors: A
authors: Geisler
authors: Xiaomin
authors: X
authors: Wang
authors: Sandra
authors: S
authors: Pinkert
authors: Tanja
authors: T
authors: Pozzuto
authors: Christina
authors: C
authors: Schwer
authors: Jens
authors: J
authors: Kurreck
authors: Stefan
authors: S
authors: Weger
authors: Roland
authors: R
authors: Vetter
authors: Wolfgang
authors: W
authors: Poller
authors: Henry
authors: H
authors: Fechner
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000258:Adenovirus Infections, Human / Q000628:therapy / Q000821:virology; D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology; D000998:Antiviral Agents; D002478:Cells, Cultured; D015536:Down-Regulation; D019084:Fluorescent Antibody Technique, Indirect; D005814:Genes, Viral; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases; D016133:Polymerase Chain Reaction; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics; D014158:Transcription, Genetic; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000235:genetics*; D014779:Virus Replication
chemical_list: D017500:Adenovirus E1A Proteins; D000998:Antiviral Agents; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; D012367:RNA, Viral; D014764:Viral Proteins; C056232:iva2 protein, adenovirus; D008156:Luciferases