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 #
5P01AI099783-02
Application #
8451991
Study Section
Special Emphasis Panel (ZAI1-RB-A)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$164,467
Indirect Cost
$46,452
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Johnsson, Per; Lipovich, Leonard; Grander, Dan et al. (2014) Evolutionary conservation of long non-coding RNAs; sequence, structure, function. Biochim Biophys Acta 1840:1063-71
Damski, Caio; Morris, Kevin V (2014) Targeted small noncoding RNA-directed gene activation in human cells. Methods Mol Biol 1173:1-10
Zhou, Jiehua; Rossi, John (2014) Cell-type-specific aptamer and aptamer-small interfering RNA conjugates for targeted human immunodeficiency virus type 1 therapy. J Investig Med 62:914-9
Saayman, Sheena; Ackley, Amanda; Turner, Anne-Marie W et al. (2014) An HIV-encoded antisense long noncoding RNA epigenetically regulates viral transcription. Mol Ther 22:1164-75
Groen, Jessica N; Capraro, David; Morris, Kevin V (2014) The emerging role of pseudogene expressed non-coding RNAs in cellular functions. Int J Biochem Cell Biol 54:350-5
Johnsson, Per; Morris, Kevin V; Grandér, Dan (2014) Pseudogenes: a novel source of trans-acting antisense RNAs. Methods Mol Biol 1167:213-26
Morris, Kevin V; Mattick, John S (2014) The rise of regulatory RNA. Nat Rev Genet 15:423-37
Roberts, Thomas C; Morris, Kevin V; Weinberg, Marc S (2014) Perspectives on the mechanism of transcriptional regulation by long non-coding RNAs. Epigenetics 9:13-20
Groen, Jessica N; Morris, Kevin V (2013) Chromatin, non-coding RNAs, and the expression of HIV. Viruses 5:1633-45
Akkina, Ramesh (2013) Human immune responses and potential for vaccine assessment in humanized mice. Curr Opin Immunol 25:403-9

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