The goal of this program is to develop cell targeted approaches to delivering small non-coding RNA directed transcriptional gene silencing and RNA directed Pddlp mediated excision as a therapeutic modality for the treatment of HIV-1 infection. We have learned that small non-coding RNAs targeted to specific loci in the HIV-1 or CCRS promoters can result in stable epigenetic silencing of HIV-1 or CCRS, which in the context of HIV-1 is refractory to viral mutation. We have also recently developed and humanized the Pdd1p DNA excision machinery from Tetrahymina thermophila and found that this system can be used to excise those loci targeted for transcriptional silencing by the small non-coding RNA. The work proposed in science core B will assist in the realization of the programs goals by: (1) developing and characterizing a new CCRS receptor targeted aptamer and (2) determining the ability of the different cell-target strategies to excise HIV-1 or CCRS from the genome of target cells and to what extent HIV-1 eludes such anti-viral targeting by viral mutation. All of the proposed approaches will be developed and mechanistically validated in vitro and in vivo. Science core B will be integral in validating the efficacy of excision and the effects of viral or CCRS promoter suppression on viral fitness.
This project will develop and characterize a new CCRS targeted aptamer as well as comprehensively assess the effects of the various targeted strategies to suppress and/or excise HIV-1 or CCRS from target cells and the ability of the virus to mutate around such selective pressures.
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|Lazar, Daniel C; Morris, Kevin V; Saayman, Sheena M (2016) The emerging role of long non-coding RNAs in HIV infection. Virus Res 212:114-26|
|Fortes, Puri; Morris, Kevin V (2016) Long noncoding RNAs in viral infections. Virus Res 212:1-11|
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|Yu, Albert D; Wang, Zichen; Morris, Kevin V (2015) Long noncoding RNAs: a potent source of regulation in immunity and disease. Immunol Cell Biol 93:277-83|
|Zhou, Jiehua; Satheesan, Sangeetha; Li, Haitang et al. (2015) Cell-specific RNA aptamer against human CCR5 specifically targets HIV-1 susceptible cells and inhibits HIV-1 infectivity. Chem Biol 22:379-90|
|Vadie, Nadia; Saayman, Sheena; Lenox, Alexandra et al. (2015) MYCNOS functions as an antisense RNA regulating MYCN. RNA Biol 12:893-9|
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