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Another major effort of my group is to develop gene therapy for HIV infection. Recent studies of the dynamics of HIV replication in patients under antiviral therapy have reaffirmed the central role of the virus in disease progression and provided a strong rationale for the development of effective, long term antiviral therapy. There are several critical steps in the development of anti-HIV gene therapy: (1) Identification/design of the most potent inhibitory gene(s); (2) Achievement of high level and persistent gene expression in relevant target cells; and (3) Efficient gene transfer into either the mature target cells or hematopoietic progenitor cells. My laboratory has focused on the use of ribozymes (catalytic RNA) to specifically cleave both afferent and efferent viral RNA during the HIV replication cycle. We showed that T-cell lines and primary lymphocytes transduced with retroviral vectors expressing an anti-HIV hairpin ribozyme from a Pol III promoter were resistant to exogenous infection with diverse strains of HIV-1. Furthermore, macrophages derived from primary CD34+ hematopoietic stem/progenitor cells were also resistant to challenge with a macrophage tropic strain of HIV-1. We also developed combinatorial vectors to minimize the chance of viral resistance as well as to increase anti-viral potency.
A clinical trial to test the safety and feasibility of this therapy in patients has begun. Currently, we are developing HIV-based gene delivery vectors to specifically target human CD4+ cells or quiescent, primitive hematopoietic stem cells.


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