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Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines; however, uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective microRNA expression now affords the possibility of engineering replicating viruses that are attenuated at the RNA level in sites of potential pathology, but retain wild-type replication activity at sites not expressing the relevant microRNA. To assess the usefulness of this approach for the DNA virus adenovirus, we have engineered a hepatocyte-safe wild-type adenovirus 5 (Ad5), which normally mediates significant toxicity and is potentially lethal in mice. To do this, we have included binding sites for hepatocyte-selective microRNA mir-122 within the 3' UTR of the E1A transcription cassette. Imaging versions of these viruses, produced by fusing E1A with luciferase, showed that inclusion of mir-122 binding sites caused up to 80-fold decreased hepatic expression of E1A following intravenous delivery to mice. Animals administered a ten-times lethal dose of wild-type Ad5 (5x10(10) viral particles/mouse) showed substantial hepatic genome replication and extensive liver pathology, while inclusion of 4 microRNA binding sites decreased replication 50-fold and virtually abrogated liver toxicity. This modified wild-type virus retained full activity within cancer cells and provided a potent, liver-safe oncolytic virus. In addition to providing many potent new viruses for cancer virotherapy, microRNA control of virus replication should provide a new strategy for designing safe attenuated vaccines applied across a broad range of viral diseases.

Original publication

DOI

10.1371/journal.ppat.1000440

Type

Journal article

Journal

PLoS Pathog

Publication Date

05/2009

Volume

5

Keywords

Adenoviridae, Adenovirus E1A Proteins, Alanine Transaminase, Amino Acid Sequence, Animals, Artificial Gene Fusion, Aspartate Aminotransferases, Binding Sites, Cell Line, Tumor, Fluorescence, Gene Expression Regulation, Viral, Hepatocytes, Humans, Liver, Liver Neoplasms, Experimental, Mice, Mice, Inbred BALB C, MicroRNAs, Molecular Sequence Data, Oncolytic Virotherapy, Tissue Distribution, Whole Body Imaging