The ability of adoptively transferred T cells to mediate in vivo anti-viral effects is now well-documented, particularly in the setting of chronic viral infections such as Epstein Barr virus and cytomegalovirus infections. The principle that adoptively transferred T lymphocytes have therapeutic promise for HIV infection is also well established. However, reproducibly harnessing this activity for chronic HIV infections to provide therapeutic benefit requires that several technical barriers be solved. Our long range goal is to obviate the need of patients to take daily antiviral medications in patients with HIV infection. Our long objective is to establish the safety of infusions of engineered CD8 and CD4 T cells, and to test for improved antiviral efficacy. In this project we will first test the hypothesis that infusions of lentiviral engineered autologous CD8 T cells that have been "converted" into CTLs by expressing TCR heterodimers that redirect specificity to HLA A2 presented gag epitopes will lead to sustained engraftment and enhanced antiviral effects. In addition, the ability to control escape mutations of the originally isolated (parental) TCR will be compared to an affinity enhanced TCR in this trial. As a complementary strategy we are currently testing the adoptive transfer of CD4 cells that are engineered for resistance to HIV infection using zinc finger nucleases to genetically edit the CCR5 locus. Based on strong preliminary data the specific aims are to: 1) Complete the pre-clinical testing and regulatory requirements necessary to open the CD8 CTL clinical trial;2) Conduct and analyze a proof of concept clinical trial to determine the safety and relative antiviral efficacy of "converted" CTLs expressing either the parental or high affinity Gag SL9 TCR in patients with HIV infection and 3) To conduct a second clinical trial testing combination therapy with CCR5 edited CD4 cells and CD8 CTLs expressing Gag SL9 TCRs in patients with HIV infection. Private sector interactions are established with Adaptimmune Ltd. and Sangamo BioSciences, Inc. Together these studies will provide a comprehensive evaluation of the safety and antiviral efficacy of engineered CD4 and CD8 T cells for HIIV/AIDS, and they will move the field forward by providing critical safety data for this new and exciting approach to control HIV infection.
In this project a form of personalized medicine, where patient CD4 and CD8 T cells will be altered in the laboratory to have (i) improved ability to control HIV infection and (ii) intrinsic resistance to infection. The clinical trials in this project will test the safety and antiviral efficacy of .this novel transfusion approach in two proof of concept clinical trials.
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|Richardson, Max W; Guo, Lili; Xin, Frances et al. (2014) Stabilized human TRIM5? protects human T cells from HIV-1 infection. Mol Ther 22:1084-95|
|Maier, Dawn A; Brennan, Andrea L; Jiang, Shuguang et al. (2013) Efficient clinical scale gene modification via zinc finger nuclease-targeted disruption of the HIV co-receptor CCR5. Hum Gene Ther 24:245-58|
|Didigu, Chukwuka A; Doms, Robert W (2012) Novel approaches to inhibit HIV entry. Viruses 4:309-24|
|Scholler, John; Brady, Troy L; Binder-Scholl, Gwendolyn et al. (2012) Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med 4:132ra53|
|Wilen, Craig B; Wang, Jianbin; Tilton, John C et al. (2011) Engineering HIV-resistant human CD4+ T cells with CXCR4-specific zinc-finger nucleases. PLoS Pathog 7:e1002020|
|Cannon, Paula; June, Carl (2011) Chemokine receptor 5 knockout strategies. Curr Opin HIV AIDS 6:74-9|
|Francica, Joseph R; Varela-Rohena, Angel; Medvec, Andrew et al. (2010) Steric shielding of surface epitopes and impaired immune recognition induced by the ebola virus glycoprotein. PLoS Pathog 6:e1001098|
|Mukherjee, Rithun; Plesa, Gabriela; Sherrill-Mix, Scott et al. (2010) HIV sequence variation associated with env antisense adoptive T-cell therapy in the hNSG mouse model. Mol Ther 18:803-11|
|June, Carl H; Blazar, Bruce R; Riley, James L (2009) Engineering lymphocyte subsets: tools, trials and tribulations. Nat Rev Immunol 9:704-16|
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