Inhibition of adenovirus infections by siRNA-mediated silencing of early and late adenoviral gene functions

Eckstein, Anne; Größl, Tobias; Geisler, Anja; Wang, Xiaomin; Pinkert, Sandra; Pozzuto, Tanja; Schwer, Christina; Kurreck, Jens; Weger, Stefan; Vetter, Roland; Poller, Wolfgang; Fechner, Henry

doi:10.1016/j.antiviral.2010.08.002

Cited by 28 publications

(39 citation statements)

References 51 publications

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“…In vitro silencing of adenoviral genes by siRNAs has been demonstrated for an adenovirus (Ad) 11 strain (2K2/507/KNIH; species B; isolated in Korea) (Chung et al, 2007), and also for a mutant strain of Ad5 (species C) lacking the E1B and E3 genes (Eckstein et al, 2010). In the case of Ad11, siRNAs directed against E1A were reported to result in an overall reduction of plaque-forming capacity.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of adenovirus multiplication by short interfering RNAs directly or indirectly targeting the viral DNA replication machinery

et al. 2012

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Section: Introductionmentioning

confidence: 99%

Inhibition of adenovirus multiplication by short interfering RNAs directly or indirectly targeting the viral DNA replication machinery

et al. 2012

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“…Alternatively, adenoviral genes other than E1A that more directly link gene expression input to virus replication output can be regulated. In this context, the DNA polymerase or IVa2 genes could be of interest, as their knockdown RNAi proved more effective than that of E1A (37,38). Similarly, aptazyme regulation of the measles virus P or L polymerase genes or of the nucleocapsid N gene may facilitate conditional virus replication, as indicated by RNAi studies (39,40).…”

Section: Discussionmentioning

confidence: 99%

Artificial riboswitches for gene expression and replication control of DNA and RNA viruses

Ketzer

Kaufmann

Engelhardt

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

100

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Aptazymes are small, ligand-dependent self-cleaving ribozymes that function independently of transcription factors and can be customized for induction by various small molecules. Here, we introduce these artificial riboswitches for regulation of DNA and RNA viruses. We hypothesize that they represent universally applicable tools for studying viral gene functions and for applications as a safety switch for oncolytic and live vaccine viruses. Our study shows that the insertion of artificial aptazymes into the adenoviral immediate early gene E1A enables small-molecule-triggered, dosedependent inhibition of gene expression. Aptazyme-mediated shutdown of E1A expression translates into inhibition of adenoviral genome replication, infectious particle production, and cytotoxicity/ oncolysis. These results provide proof of concept for the aptazyme approach for effective control of biological outcomes in eukaryotic systems, specifically in virus infections. Importantly, we also demonstrate aptazyme-dependent regulation of measles virus fusion protein expression, translating into potent reduction of progeny infectivity and virus spread. This not only establishes functionality of aptazymes in fully cytoplasmic genetic systems, but also implicates general feasibility of this strategy for application in viruses with either DNA or RNA genomes. Our study implies that gene regulation by artificial riboswitches may be an appealing alternative to Tet-and other protein-dependent gene regulation systems, based on their small size, RNA-intrinsic mode of action, and flexibility of the inducing molecule. Future applications range from gene analysis in basic research to medicine, for example as a safety switch for new generations of efficiency-enhanced oncolytic viruses.

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“…In recent years, another approach to inhibit HAdV DNA replication has emerged by using short interfering RNAs (siRNAs) [93,94]. Several siRNAs targeting different transcripts have been evaluated for their potential antiHAdV activity.…”

Section: Adenovirus Dna Replicationmentioning

confidence: 99%

“…The replicative cycle of human adenovirus (HAdV) is a highly coordinated multistage process and any of these steps could be used as a target for the design of new antiHAdV agents. For references relevant to binding and internalization, see [73,[75][76][77][78][79], for endosomal escape, trafficking, and docking, see [51,52,[82][83][84][85][86], for gene expression, see [88,[93][94][95], for DNA replication, see [7,19,50], and for assembly, maturation, and release, see [48,[97][98][99]. …”

mentioning

confidence: 99%

Antiadenovirus drug discovery: potential targets and evaluation methodologies

Martínez-Aguado

Serna-Gallego

Marrugal-Lorenzo

et al. 2015

Drug Discovery Today

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Inhibition of adenovirus infections by siRNA-mediated silencing of early and late adenoviral gene functions

Cited by 28 publications

References 51 publications

Inhibition of adenovirus multiplication by short interfering RNAs directly or indirectly targeting the viral DNA replication machinery

Inhibition of adenovirus multiplication by short interfering RNAs directly or indirectly targeting the viral DNA replication machinery

Artificial riboswitches for gene expression and replication control of DNA and RNA viruses

Antiadenovirus drug discovery: potential targets and evaluation methodologies

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