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)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI099783-03
Application #
8637922
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
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
Zhou, Jiehua; Lazar, Daniel; Li, Haitang et al. (2018) Receptor-targeted aptamer-siRNA conjugate-directed transcriptional regulation of HIV-1. Theranostics 8:1575-1590
Astakhova, Kira; Ray, Roslyn; Taskova, Maria et al. (2018) ""Clicking"" Gene Therapeutics: A Successful Union of Chemistry and Biomedicine for New Solutions. Mol Pharm 15:2892-2899
Shevchenko, Galina; Morris, Kevin V (2018) All I's on the RADAR: role of ADAR in gene regulation. FEBS Lett 592:2860-2873
Shrivastava, Surya; Charlins, Paige; Ackley, Amanda et al. (2018) Stable Transcriptional Repression and Parasitism of HIV-1. Mol Ther Nucleic Acids 12:12-18
Johnsson, Per; Lister, Nicholas; Shevchenko, Galina et al. (2017) Reply to Liu et al.: Yin and yang of PTEN regulation. Proc Natl Acad Sci U S A 114:E10512-E10513
Lister, Nicholas; Shevchenko, Galina; Walshe, James L et al. (2017) The molecular dynamics of long noncoding RNA control of transcription in PTEN and its pseudogene. Proc Natl Acad Sci U S A 114:9942-9947
Hewson, Chris; Morris, Kevin V (2016) Form and Function of Exosome-Associated Long Non-coding RNAs in Cancer. Curr Top Microbiol Immunol 394:41-56
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
Saayman, Sheena M; Lazar, Daniel C; Scott, Tristan A et al. (2016) Potent and Targeted Activation of Latent HIV-1 Using the CRISPR/dCas9 Activator Complex. Mol Ther 24:488-98
Weinberg, Marc S; Morris, Kevin V (2016) Transcriptional gene silencing in humans. Nucleic Acids Res 44:6505-17

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