potent inhibition of HIV-1 infection in cultured cells. We will extend our analyses of these constructs to primary CD34+ cells and T-lymphocytes as part of specific aim 1.
In aim 2 further analyses of the functional role of HIV-1 RNA trafficking through the nucleolus will be explored. Specifically, we will investigate the possibility that 2'0-methyl covalent backbone modifications in the R region of HN-1 RNA are guided by a cellular small nucleolar RNA. We will engineer a small nucleolar RNA to misdirect 2'0 methylations to specific sites of protein interaction in the HIV TAR and Rl3E elements. Finally, an in vivo SELEX scheme will be developec to select for new targets, both in HIV-1 and cellular RNAs using a randomized binding arm library of nucleolar localized ribozymes. The results of the work proposed in this aim should extend our knowledge of the functional role of HIV RNA and protein trafficking through tht nucleolus, and provide new ribozymes and other inhibitory RNAs for inhibition of HIV-1 infection. The overall objective of this work is tc enhance our understanding of HIV RNA localization via the use of ribozymes, and to identify the best ribozyme-HIV target strategies for future use in human gene therapy. I
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