Retroviral Vectors Post Entry Events and Genomic Alterations 英文参考文献.docVIP

Viruses 2011, 3, 429-455; doi:10.3390/v3050429 OPEN ACCESS viruses ISSN 1999-4915 /journal/viruses Review Retroviral Vectors: Post Entry Events and Genomic Alterations Ali Nowrouzi 1,2, Hanno Glimm 1,2, Christof von Kalle 1,2 * and Manfred Schmidt 1,2 * 1 Department of Translational Oncology, German Cancer Research Center, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany; E-Mail: ali.nowrouzi@nct-heidelberg.de (A.N.) National Center for Tumor Diseases, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany 2 * Authors to whom correspondence should be addressed; E-Mails: Christof.kalle@nct-heidelberg.de (C.v.K.); Manfred.schmidt@nct-heidelberg.de (M.S.); Tel.: +49-6221-56-6991; +49-6221-42-1600; Fax: +49-6221-56-6930; +49-6221-42-1611. Received: 9 February 2011; in revised form: 24 March 2011 / Accepted: 5 April 2011 / Published: 29 April 2011 Abstract: The curative potential of retroviral vectors for somatic gene therapy has been demonstrated impressively in several clinical trials leading to sustained long-term correction of the underlying genetic defect. Preclinical studies and clinical monitoring of gene modified hematopoietic stem and progenitor cells in patients have shown that biologically relevant vector induced side effects, ranging from in vitro immortalization to clonal dominance and oncogenesis in vivo, accompany therapeutic efficiency of integrating retroviral gene transfer systems. Most importantly, it has been demonstrated that the genotoxic potential is not identical among all retroviral vector systems designed for clinical application. Large scale viral integration site determination has uncovered significant differences in the target site selection of retrovirus subfamilies influencing the propensity for inducing genetic alterations in the host genome. In this review we will summarize recent insights gained on the mechanisms of insertional mutagenesis based