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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01AI099783-03
Application #
8637922
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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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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