Lentiviral vectors are among the most efficient gene transfer tools for dividing and non-dividing cells. However, insertional mutagenesis has been observed in clinical trials with oncoretroviral vectors and this has prompted detailed study of genotoxicty of all integrating vectors. For many applications, avoiding integration is the most straightforward approach to overcome this problem and is facilitated by the extensive studies of the integrating mechanisms of lentiviruses. Indeed, non-integrating lentiviral vectors have been developed by mutating the integrase gene or by modifying the attachment sequences of the LTRs. In this review, we first consider on the toxicity associated with integration and on lentivirus integrase biology, and discuss the implications of integrase mutant studies for the development of non-integrating lentiviral vectors. We review published data concerning non-integrating lentiviral vectors with particular focus on their residual integration and transgene expression efficiency. Finally, the latest advances in the development of genetic engineering tools derived from non-integrating lentiviral vectors are presented.
Keywords: HIV, integrase, episome, genotoxicity, gene therapy, gene editing, site-specific recombinase, biosafety
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