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.