Integration of Retroviruses into a Predetermined Site
Retroviruses are currently the preferred vehicle for transduction of mammalian cells to be used in gene therapy. However, safety concerns limit their use at present to ex vivo procedures. One of the ultimate challenges for gene therapy will be to develop a vehicle for gene delivery that can be used in vivo. The vector of choice is likely to remain a retrovirus; one of its major advantages being that it can link therapeutic sequences to the host chromosome with stable covalent bonds. However, this positive attribute of retroviral vectors is potentially one of its major drawbacks. The integration of the viral genome, catalyzed by the enzyme integrase (IN), shows no discernible sequence specificity. There is the danger that such unpredictable integration of retroviral sequences could activate proto oncogenes potentially leading to carcinogenisis, or conversely, could lead to gene inactivation. However, integration is not completely random. Several studies have indicated that in vivo, many mouse retroviruses tend to integrate into DNAseI hypersensitive or transcriptionally active sites suggesting that there may be a bias towards open chromatin structures1,2,3,4,5. An even more pronounced bias in target site selection has been observed for retrotransposable elements such as Ty1 and Ty3 of yeast. Emerging evidence suggests that target site selection may be governed by host factors that associate with retroviral/retrotransposable element integration machinery6. By understanding the mechanism of target site selection by retroviruses, one may be able to modulate the process in such a way that retroviral integration can be directed to predetermined safe sites on the chromosome.
KeywordsHuman Immunodeficiency Virus Type Host Chromosome Viral cDNA Retrotransposable Element Preintegration Complex
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