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Silencing of gene expression: implications for design of retrovirus vectors
Author(s) -
Pannell Dylan,
Ellis James
Publication year - 2001
Publication title -
reviews in medical virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.06
H-Index - 90
eISSN - 1099-1654
pISSN - 1052-9276
DOI - 10.1002/rmv.316
Subject(s) - gene silencing , biology , rna interference , dna methylation , retrovirus , vector (molecular biology) , viral vector , transgene , genetics , gene , microbiology and biotechnology , gene expression , rna , recombinant dna
Transcriptional silencing of retroviruses poses a major obstacle to their use as gene therapy vectors. Silencing is most pronounced in stem cells which are desirable targets for therapeutic gene delivery. Many vector designs combat silencing through cis ‐modifications of retroviral vector sequences. These designs include mutations of known retroviral silencer elements, addition of positive regulatory elements and insulator elements to protect the transgene from negative position effects. Similar strategies are being applied to lentiviral vectors that readily infect non‐dividing quiescent stem cells. Collectively these cis ‐modifications have significantly improved vector design but optimal expression may require additional intervention to escape completely the trans ‐factors that scan for foreign DNA, establish silencing in stem cells and maintain silencing in their progeny. Cytosine methylation of CpG sites was proposed to cause retroviral silencing over 20 years ago. However, several studies provide evidence that retrovirus silencing acts through methylase‐independent mechanisms. We propose an alternative silencing mechanism initiated by a speculative stem cell‐specific ‘somno‐complex’. Further understanding of retroviral silencing mechanisms will facilitate better gene therapy vector design and raise new strategies to block transcriptional silencing in transduced stem cells. Copyright © 2001 John Wiley & Sons, Ltd.