Targeting of cytotoxic T-cells to HIV infected cells
Final Report Abstract
Experimental and clinical data present good evidence that T-cell mediated immune responses play 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 cells. Chimeric 5-Helix-zeta receptor genes were constructed and characterized and we demonstrated that 5-Helix-zeta does not support entry of HIV into cells. Attempts to stably transduce the constructs into human T lymphocytes were disappointing and alternatively effector cell lines were generated based on NK-92 cells. Specific cytotoxicity of genetically modified NK-cells towards HIV Env expressing cells or HIV infected cells were tested in vitro and showed a specific killing activity. We were able to show proof of concept for this approach.
Publications
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Siegert S, Thaler S, Wagner R, Schnierle BS. Assessment of HIV-1 entry inhibitors by MLV/HIV-1 pseudotyped vectors. AIDS Res Ther. 2:7, (2005).
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Siegert S., Schnierle P. and Schnierle BS. Novel anti-viral therapy: Drugs that block HIV entry at different target sites. Mini-Reviews in Medicinal Chemistry 6: 557-62 (2006)
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Thomas Schulz (Promotion) Gentherapie zur Behandlung der HIV-Infektion und des kutanen T-Zell Lymphoms Biowissenschaften, Universität Frankfurt, 2007
