Recent reports demonstrate that individuals lacking a functional CCR-5 chemokine receptor gene are resistant to infection with HIV-1 as CCR-5 is the coreceptor for macrophage-tropic HIV-1 (the most prevalent phenotype of transmitted HIV). The possibility of using chemokines therapeutically to block infection is being explored by a number of laboratories. However, the use of bioactive chemokines and the uncertain levels of expression that would have to be obtained are drawbacks to this approach. Therefore, the applicant seeks an alternative approach. The Principal Investigator s laboratory has demonstrated that lymphocytes expressing an intrakine (ER-retained chemokine, MIP-1a or RANTES) blocks cell surface expression of the CCR-5, and renders these cells resistant to infection with macrophage-tropic HIV-1. The goal of this proposal is to explore the potential use of """"""""intrakines"""""""" in human gene therapy. Murine retroviral vectors and packaging cell lines will be developed and transduction procedures established. Recombinant retroviruses will be tested for the ability to block HIV infection in primary human lymphocytes. In addition, myelomonocytic cells derived by transduction of human CD34+ stem cells will be assessed for resistance to macrophage-tropic HIV-1. Stromal cell-derived factor 1 (SDF-1) which can inactivate the T cell-tropic coreceptor CXCR4 will also be tested in primary lymphocytes and stem cells with the goal that co-expression of both intrakines may block both T cell and macrophage-tropic viruses. Potential toxicity will be assessed in a mouse model following the introduction of transduced progenitor cells.
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