Targeting of cytotoxic T-cells to HIV infected cells

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Experimental and clinical data present good evidence that T-cell mediated immune response plays a major role in controlling human immunodeficiency virus (HIV) infection. Cytotoxic T-cells can be engineered to express chimeric receptors directed against HIV infected cells and can serve as HIV specific, MHC-unrestricted effector cells. We will use the designed entry inhibitor 5-Helix to redirect cytotoxic effector cells to HIV infected cells. This HIV binding domain has several advantages over previously used ligands, like CD4 or antibody fragments: 5-Helix mimics the carboxyl-terminal region of the gp41 envelope glycoprotein ectodomain but lacks one helix of the six-helix bundle. It is therefore a high affinity binding domain for gp41 and binds a wide variety of HIV strains. Most importantly, surface exposure of 5-Helix does not support entry of HIV into the cells. A chimeric 5-Helix-zeta receptor gene will be constructed and stably transduced into human T lymphocytes. Specific cytotoxicity of genetically modified T-cells towards HIV Env expressing cells or HIV infected cells will be first tested in vitro and subsequently in vivo. A mouse model with HIV Env expressing cells will be established. The project should prove the feasibility of this targeting approach and should provide the pre-clinical requirements for a future clinical application of this strategy. Gene mo dified autologous T lymphocytes should eliminate residual HIV infected cells in patients under HAART (highly active antiretroviral therapy) treatment or during STI (structured treatment interruption).