? The overall hypothesis to be tested in this proposal is that small interfering RNAs directed to HIV-1 can serve as a therapy for HIV-1 disease. RNA interference is an evolutionarily conserved mechanism whereby small double stranded RNAs induce sequence specific silencing of homologous genes. The application of siRNA technology consists of chemical or recombinant 21- 29 nucleotide length double strand RNAs that act to degrade the RNA template to which it has homology, siRNAs have been utilized for """"""""knock-out"""""""" of various cellular genes. Recently siRNA directed to HIV-1 sequences have been shown to inhibit HIV-1 replication in cell culture. Other """"""""genetic immunization"""""""" approaches to HIV-1 disease successfully inhibited HIV-1 in cell culture, but extension of the studies to humans had resulted in minimal efficacy. It is unclear whether the lack of success is due to the gene therapeutic reagent itself, the delivery system, or both. Thus, it is critical that genetic immunization approaches be thoroughly modeled in systems where variables can be tested and optimized to gain an understanding of the most effective parameters for inhibition. We propose to model siRNA to HIV-1 and CCR5 using lentiviral vectors for stable delivery. ? ? ?
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