A quantitative comparison of anti-HIV gene therapy delivered to hematopoietic stem cells versus CD4+ T cells

• Published in: PLoS computational biology 2014-06, Vol.10 (6), p.e1003681-e1003681
• Main Authors: Savkovic, Borislav, Nichols, James, Birkett, Donald, Applegate, Tanya, Ledger, Scott, Symonds, Geoff, Murray, John M
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Antigens, CD34; Biology and Life Sciences; Bone marrow; Care and treatment; CD4-Positive T-Lymphocytes - immunology; Comparative analysis; Computational Biology; Computer Simulation; Disease Progression; Gene therapy; Gene Transfer Techniques; Genetic aspects; Genetic Therapy; Health aspects; Hematopoietic Stem Cells - immunology; HIV; HIV Fusion Inhibitors; HIV infection; HIV Infections - therapy; HIV Infections - virology; HIV-1 - genetics; Human immunodeficiency virus; Humans; Medicine and Health Sciences; Models, Biological; Physical Sciences; Receptors, CCR5; Recombinant Fusion Proteins - genetics; Stem cells; T cells
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1003681

Gene therapy represents an alternative and promising anti-HIV modality to highly active antiretroviral therapy. It involves the introduction of a protective gene into a cell, thereby conferring protection against HIV. While clinical trials to date have delivered gene therapy to CD4+T cells or to CD34+ hematopoietic stem cells (HSC), the relative benefits of each of these two cellular targets have not been conclusively determined. In the present analysis, we investigated the relative merits of delivering a dual construct (CCR5 entry inhibitor + C46 fusion inhibitor) to either CD4+T cells or to CD34+ HSC. Using mathematical modelling, we determined the impact of each scenario in terms of total CD4+T cell counts over a 10 year period, and also in terms of inhibition of CCR5 and CXCR4 tropic virus. Our modelling determined that therapy delivery to CD34+ HSC generally resulted in better outcomes than delivery to CD4+T cells. An early one-off therapy delivery to CD34+ HSC, assuming that 20% of CD34+ HSC in the bone marrow were gene-modified (G+), resulted in total CD4+T cell counts ≥ 180 cells/ µL in peripheral blood after 10 years. If the uninfected G+ CD4+T cells (in addition to exhibiting lower likelihood of becoming productively infected) also exhibited reduced levels of bystander apoptosis (92.5% reduction) over non gene-modified (G-) CD4+T cells, then total CD4+T cell counts of ≥ 350 cells/ µL were observed after 10 years, even if initially only 10% of CD34+ HSC in the bone marrow received the protective gene. Taken together our results indicate that: 1.) therapy delivery to CD34+ HSC will result in better outcomes than delivery to CD4+T cells, and 2.) a greater impact of gene therapy will be observed if G+ CD4+T cells exhibit reduced levels of bystander apoptosis over G- CD4+T cells.