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Viruses 2014, 6(11), 4140-4164;

Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy

Department of Immunology, Wright-Fleming Institute, Imperial College London, London W2 1PG, UK
Author to whom correspondence should be addressed.
Received: 4 August 2014 / Revised: 9 October 2014 / Accepted: 21 October 2014 / Published: 31 October 2014
(This article belongs to the Special Issue Retroviral Vectors)
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Retroviral vectors have been successfully used therapeutically to restore expression of genes in a range of single-gene diseases, including several primary immunodeficiency disorders. Although clinical trials have shown remarkable results, there have also been a number of severe adverse events involving malignant outgrowth of a transformed clonal population. This clonal expansion is influenced by the integration site profile of the viral integrase, the transgene expressed, and the effect of the viral promoters on the neighbouring host genome. Infection with the pathogenic human retrovirus HTLV-1 also causes clonal expansion of cells containing an integrated HTLV-1 provirus. Although the majority of HTLV-1-infected people remain asymptomatic, up to 5% develop an aggressive T cell malignancy. In this review we discuss recent findings on the role of the genomic integration site in determining the clonality and the potential for malignant transformation of cells carrying integrated HTLV-1 or gene therapy vectors, and how these results have contributed to the understanding of HTLV-1 pathogenesis and to improvements in gene therapy vector safety. View Full-Text
Keywords: HTLV-1; gene therapy; gammaretroviral vector; integration site HTLV-1; gene therapy; gammaretroviral vector; integration site

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Niederer, H.A.; Bangham, C.R.M. Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy. Viruses 2014, 6, 4140-4164.

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