As the field of gene therapy has developed, applications to treatment of infectious diseases, such as HIV-1 infection, have been explored. The hematopoietic stem cells (HSC) contained in either bone marrow or the umbilical cord blood from newborns represent a logical target cell for gene therapy of AIDS. HSC produce the full spectrum of cells involved in AIDS pathogenesis: T lymphocytes, monocytes, macrophages, dendritic cells, and microglial (17,18). HSC are long-lived, producing new progeny cells for the life of the recipient after transplant. Therefore, insertion of a gene capable of conferring resistance to HIV-1 into hematopoietic stem cells could result in that gene being present in the mature T lymphocytes and other HIV-1-susceptible cells which are produced. Recent incremental improvements in Moloney murine leukemia virus (MLV) retroviral-mediated gene transfer into human hematopoietic stem cells (HSC) have been achieved (e.g. 10%, up from the previous ceiling of 0.1- 1.0%). However, even higher levels of gene transduction of stem cells are likely to be needed for applications to AIDS. Lentiviral vectors hold the promise of producing increased transduction of HSC, due to their ability to transduce quiescent cells. For anti-HIV-1 genes, the requisite expression parameters will vary, based on specific aspects of the anti- HIV-1 gene product (e.g. active as RNA or translated into protein). To improve methodologies for gene therapy of HIV-1 using hematopoietic stem cells, this project (#1) will be highly interactive with the other Projects and Cores. We will work with Dr. Yee to evaluate the efficacy of novel lentiviral vectors for gene delivery to primitive human hematopoietic progenitor and stem cells. We will work with Dr. Rossi to evaluate gene expression and HIV-1 inhibition by novel expression cassettes for anti-HIV-1 genes. We will also continue to translate the findings form these basic projects into clinical trials, both with preclinical studies as well as with performing the stem cell transductions for clinical trials. These studies will contribute to fundamental advances in the techniques for gene delivery and expression and to their evaluation in subjects with HIV-1 infection.
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