title: A quantitative comparison of anti-HIV gene therapy delivered to hematopoietic stem cells versus CD4+ T cells.
abstract: 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.
authors.affiliation: School of Mathematics and Statistics, University of New South Wales, Sydney, Australia.
authors.forename: Borislav
authors.initials: B
authors.lastname: Savkovic
authors.affiliation: School of Mathematics and Statistics, University of New South Wales, Sydney, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Nichols
authors.affiliation: Department of Clinical Pharmacology, Flinders University, Adelaide, Australia.
authors.forename: Donald
authors.initials: D
authors.lastname: Birkett
authors.affiliation: Kirby Institute, University of New South Wales, Sydney, Australia.
authors.forename: Tanya
authors.initials: T
authors.lastname: Applegate
authors.affiliation: Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Ledger
authors.affiliation: St Vincent's Centre for Applied Medical Research, Darlinghurst, New South Wales, Sydney, Australia; Calimmune Pty Ltd, Darlinghurst, New South Wales, Australia.
authors.forename: Geoff
authors.initials: G
authors.lastname: Symonds
authors.affiliation: School of Mathematics and Statistics, University of New South Wales, Sydney, Australia.
authors.forename: John M
authors.initials: JM
authors.lastname: Murray
mesh_terms: D018952:Antigens, CD34; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019295:Computational Biology; D003198:Computer Simulation; D018450:Disease Progression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D023581:HIV Fusion Inhibitors; D015658:HIV Infections / Q000628:therapy / Q000821:virology; D015497:HIV-1 / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D008954:Models, Biological; D019713:Receptors, CCR5; D011993:Recombinant Fusion Proteins / Q000235:genetics
chemical_list: D018952:Antigens, CD34; C515020:C46 HIV-1 fusion inhibitory peptide; C584933:CCR5 protein, human; D023581:HIV Fusion Inhibitors; D019713:Receptors, CCR5; D011993:Recombinant Fusion Proteins