Abstract
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.
Highlights
Why Is the Retroviral Integration Site Important?In both the germline and in somatic cells, retroviruses can integrate and persist in humans for years
Certain host genomic features are moderately favoured, in analysing over 250,000 integration sites of Human T-cell Lymphotropic Virus type 1 (HTLV-1) in both in vitro and in vivo infection [39,55,56,57,58], we have found no evidence of recurrent proviral integration sites or strong clusters (“hot spots”) of integration sites, in contrast to the hot spots reported in HIV-1 infection [53]
Expansion of gene therapy vector transduced cells can be influenced by insertional mutation, or advantages conferred by certain transgenes, or by the engraftment potential of the cell
Summary
In both the germline (endogenous retroviruses) and in somatic cells (exogenous viruses; gene therapy vectors), retroviruses can integrate and persist in humans for years. Each retrovirus has its own particular characteristics of integration site preference and interaction with the host genome. The human deltaretrovirus Human T-cell Lymphotropic Virus type 1 (HTLV-1) is maintained in T lymphocytes by continued replication of infected cells for the lifetime of the infected individual. Retroviral and lentiviral vector integration sites are likewise maintained by replication of transduced cells for months or years in human recipients. Persistent proliferation can lead to selective expansion or survival of certain transduced or infected cell clones, and certain clones may undergo uncontrolled proliferation, leading to malignant disease. In this review we consider the interactions between the host genome and both HTLV-1 and retroviral gene therapy vectors, and consider how work from each field can inform the other
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