Despite significant advances in the development of new antiretroviral drugs for the treatment of HIV-1 infection, elimination of HIV-1 latent sanctuaries and the ability to discontinue HAART are not practically feasible since the viral loads rebound upon cessation of treatment. The reservoir of latently-infected, resting CD4+ T cells is extremely long-lived and can persist for decades in patients receiving antiretroviral therapy. The complete elimination of HIV-1 within a patient will therefore likely require novel clinical approaches to purge the reservoir of latently infected cells. We have shown that combinations of pharmacologic agents act synergistically to activate transcription of a broad spectrum of clinically relevant HIV strains. We propose to extend these studies by testing the latency activation potential of small activating RNAs (saRNAs), which are targeted to promoter regions and activate transcription by guiding epigenetic changes in promoter regions. These saRNAs will be tested both as a stand-alone mechanism for latency activation as well as in combination with select pharmacologic agents known to activate latent viral reservoirs. Once viral transcription is activated viral proteins are made, providing selective therapeutic targets fr targeted therapies. We propose to exploit the expression of the HIV-1 envelope protein (gp120) on the surface of infected cells as a target for aptamer mediated delivery of cytotoxic small interfering RNAs (siRNAs) which will selectively eradicate cells harboring actively replicating HIV-1. The proposed approaches are designed to optimize latency activation and subsequently purge patients of their HIV infected reservoirs. We propose to test these novel strategies in cell culture and in a humanized mouse model that supports active and latent HIV-1 infection. If successful, the proposed approaches will create a new paradigm for the eradication of HIV- 1 infection.

Public Health Relevance

Latent reservoirs of infected cells pose the greatest obstacle to curing patients of HIV-1. The proposed studies will test new approaches for activation of latent virus replication in vitro and in vivo. The long term goal of these studies is the establishment of a method for activation of latent virus followed by selective purging of these cells from infected individuals, ultimately leading to a cure from HIV-1 infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL074704-09
Application #
8411497
Study Section
Special Emphasis Panel (ZRG1-AARR-E (04))
Program Officer
Mitchell, Phyllis
Project Start
2003-07-01
Project End
2016-05-31
Budget Start
2012-08-10
Budget End
2013-05-31
Support Year
9
Fiscal Year
2012
Total Cost
$426,191
Indirect Cost
$112,509
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Yoon, Sorah; Rossi, John J (2017) Future strategies for the discovery of therapeutic aptamers. Expert Opin Drug Discov 12:317-319
Zhou, Jiehua; Rossi, John (2017) Aptamers as targeted therapeutics: current potential and challenges. Nat Rev Drug Discov 16:181-202
Song, Min-Sun; Rossi, John J (2017) Molecular mechanisms of Dicer: endonuclease and enzymatic activity. Biochem J 474:1603-1618
Yoon, Sorah; Armstrong, Brian; Habib, Nagy et al. (2017) Blind SELEX Approach Identifies RNA Aptamers That Regulate EMT and Inhibit Metastasis. Mol Cancer Res 15:811-820
Bobbin, Maggie L; Rossi, John J (2016) RNA Interference (RNAi)-Based Therapeutics: Delivering on the Promise? Annu Rev Pharmacol Toxicol 56:103-22
Liu, Xiaoxuan; Liu, Cheng; Zhou, Jiehua et al. (2015) Promoting siRNA delivery via enhanced cellular uptake using an arginine-decorated amphiphilic dendrimer. Nanoscale 7:3867-75
Takahashi, Mayumi; Burnett, John C; Rossi, John J (2015) Aptamer-siRNA chimeras for HIV. Adv Exp Med Biol 848:211-34
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
Zhang, Xizhe; Li, Haitang; Burnett, John C et al. (2014) The role of antisense long noncoding RNA in small RNA-triggered gene activation. RNA 20:1916-28
Song, Min-Sun; Rossi, John J (2014) The anti-miR21 antagomir, a therapeutic tool for colorectal cancer, has a potential synergistic effect by perturbing an angiogenesis-associated miR30. Front Genet 4:301

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