AbstractRetroviral 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 siteHTLV-1; gene therapy; gammaretroviral vector; integration site►▼ Figures
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MDPI and ACS Style
Niederer, H.A.; Bangham, C.R.M. Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy. Viruses2014, 6, 4140-4164.
Niederer HA, Bangham CRM. Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy. Viruses. 2014; 6(11):4140-4164.Chicago/Turabian Style
Niederer, Heather A.; Bangham, Charles R.M. 2014. "Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy." Viruses 6, no. 11: 4140-4164.
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Clonal selection is a part of human immune response where specific B or T-helper lymphocytes are chosen to undergo clonal expansion
B-lymphocytes and T-helper lymphocytes have unique and specific antigen receptors on their cell surface membranes. Each cell will have a slightly different type of antigen receptor. These cells will interact with pathogen antigen presenting cells, such as the pathogen iteslf, macropahges (that have ingested a pathogen and present the pathogens antigens on it's own cell surface membrane), or infected human cells, to see if their antigen receptors match the antigens. Once a match has been found, the cell that has the correct antigen receptor will undergo clonal expansion, where the cell will makes millions of copies of itself through mitosis.
The principle is important because B-lymphocytes eventaully differentiate and go on to create unique antibodies that target the specific antigens on pathogens and destroy them to fight the infection. Large amounts of energy and resources would be wasted creating antibodies that don't fit antigens on the pathogen if T or B lymphocytes without the corresponding antigen receptor were chosen to replicate/go through clonal expansion.