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Development of Cell-type specific anti-HIV gp120 aptamers for siRNA delivery
Published on: June 23, 2011
Cell-specific RNA aptamer against human CCR5 specifically targets HIV-1 susceptible cells and inhibits HIV-1
Jiehua Zhou1, Sangeetha Satheesan2, Haitang Li1
1Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Abstract:
The C-C chemokine receptor type 5 (CCR5) is a receptor expressed by T cells and macrophages that serves as a coreceptor for macrophage-tropic HIV-1. Loss of CCR5 is associated with resistance to HIV-1. Here, we combine the live-cell-based SELEX with high-throughput sequencing technology to generate CCR5 RNA aptamers capable of specifically targeting HIV-1 susceptible cells (as small interfering RNA [siRNA] delivery agent) and inhibiting HIV-1 infectivity (as antiviral agent) via block of the CCR5 required for HIV-1 to enter cells. One of the best candidates, G-3, efficiently bound and was internalized into human CCR5-expressing cells. The G-3 specifically neutralized R5 virus infection in primary peripheral blood mononuclear cells, and in vivo generated human CD4(+) T cells with a nanomolar inhibitory concentration 50%. G-3 was also capable of transferring functional siRNAs to CCR5-expressing cells. Collectively, the cell-specific, internalizing, CCR5-targeted aptamers and aptamer-siRNA conjugates offer promise for overcoming some of the current challenges of drug resistance in HIV-1 by providing cell-type- or tissue-specific delivery of various therapeutic moieties.
Insights
Researchers developed novel RNA aptamers targeting the CCR5 receptor to block HIV-1 entry into susceptible cells. These aptamers, like G-3, show potential as antiviral agents and siRNA delivery vehicles for HIV-1 therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Virology
Background:
- C-C chemokine receptor type 5 (CCR5) is crucial for HIV-1 entry into T cells and macrophages.
- CCR5 antagonists offer a strategy to inhibit HIV-1 infection and combat drug resistance.
Purpose of the Study:
- To generate and characterize novel RNA aptamers targeting CCR5 for HIV-1 therapy.
- To evaluate aptamers as antiviral agents and as delivery vehicles for small interfering RNA (siRNA).
Main Methods:
- Combined live-cell-based SELEX with high-throughput sequencing to discover CCR5-specific RNA aptamers.
- Assessed aptamer binding, internalization, and neutralization of R5 HIV-1 in vitro and in vivo.
- Investigated aptamer-mediated siRNA delivery to CCR5-expressing cells.
Main Results:
- Identified G-3, a potent RNA aptamer that binds and internalizes into CCR5-expressing cells.
- G-3 demonstrated specific neutralization of R5 HIV-1 in primary cells and human CD4(+) T cells.
- G-3 successfully delivered functional siRNAs into target cells.
Conclusions:
- CCR5-targeted aptamers offer a promising strategy for cell-specific delivery of therapeutics.
- Aptamer-siRNA conjugates present a novel approach to combat HIV-1 infection and drug resistance.
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