Human Immunodeficiency Virus type 1 (HIV) ravages the immune system of infected individuals by prolonged latent infection of immune cells. An understanding of the molecular mechanisms regulating latency could lead to strategies aimed at either inhibiting this process and purging cellular reservoirs of HIV. We have learned that an HIV expressed antisense long non-coding RNA (lncRNA) functions in epigenetically modulating viral transcription. In this project we propose to mechanistically validate the role of this lncRNA in driving viral latency, determine what host proteins are involved in the process, and develop an innovative strategy to treat cells such that the virus cannot enter latency. The completion of this project will significantly expand our current understanding of HIV infection and provide new avenues to modulate viral expression that may prove relevant in both therapeutic strategies to purge viral reservoirs as well as possible approaches to develop an HIV vaccine.

Public Health Relevance

This project will develop and mechanistically characterize an innovative method to deliver non-coding RNAs capable of transcriptionally regulating the ability of HIV to enter viral latency. This method may also lead to significant insights into how non-coding RNAs regulate gene expression, which could also prove useful beyond the scope of HIV, in areas such as cancer and genetic diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI111139-02
Application #
8895833
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Poon, Betty
Project Start
2014-07-22
Project End
2016-03-31
Budget Start
2015-07-01
Budget End
2016-03-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Castino, M R; Baker-Andresen, D; Ratnu, V S et al. (2018) Persistent histone modifications at the BDNF and Cdk-5 promoters following extinction of nicotine-seeking in rats. Genes Brain Behav 17:98-106
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
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
Trakman, Laura; Hewson, Chris; Burdach, Jon et al. (2016) RNA Directed Modulation of Phenotypic Plasticity in Human Cells. PLoS One 11:e0152424

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