p53-dependent antiviral RNA-interference facilitates tumor-selective viral replication.
RNA-interference (RNAi) is a potent tool for specific gene silencing. In this study, we developed an adenovirus for conditional replication in p53-dysfunctional tumor cells that uses p53-selective expression of a microRNA-network directed against essential adenoviral genes. Compared to a control virus that expressed a scrambled microRNA-network, antiviral RNAi selectively attenuated viral replication in cells with transcriptionally active p53, but not in p53-dysfunctional tumor cells where both viruses replicated equivalently. Since these results were confirmed by an in vivo comparison of both viruses after infection of p53-knockout and normal mice, we could demonstrate that attenuated replication was indeed a result of p53-selective exhibition of antiviral RNAi. Addressing the therapeutic applicability, we could show that the application of RNAi-controlled virus efficiently lysed p53-dysfunctional tumors in vitro and in vivo but resulted in drastically reduced load of virus-DNA in the liver of treated mice. We have generated a broadly applicable adenovirus for selective destruction of p53-dysfunctional tumors and thereby demonstrate that virus-encoded RNAi-networks represent an efficient and versatile tool to modify viral functions. RNAi-networks can be applied to all transcriptionally regulated DNA-viruses to remodulate viral tropism and thus provide means to generate specifically replicating vectors for clinical applications.
Gürlevik
Engin
E
Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Carl Neuberg Str. 1, 30625 Hannover, Germany.
Woller
Norman
N
Schache
Peter
P
Malek
Nisar P
NP
Wirth
Thomas C
TC
Zender
Lars
L
Manns
Michael P
MP
Kubicka
Stefan
S
Kühnel
Florian
F
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000032:analysis; D005814:Genes, Viral; D006801:Humans; D008099:Liver / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000737:chemistry; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D004279:DNA, Viral; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53