51. Cell-specific RNA aptamer against human CCR5 specifically targets HIV-1 susceptible cells and inhibits HIV-1 infectivity.
- Author
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Zhou J, Satheesan S, Li H, Weinberg MS, Morris KV, Burnett JC, and Rossi JJ
- Subjects
- Aptamers, Nucleotide genetics, Aptamers, Nucleotide metabolism, Base Sequence, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes virology, Cell Culture Techniques, Cells, Cultured, HIV Infections immunology, HIV Infections virology, HIV-1 pathogenicity, Humans, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear virology, Macrophages immunology, Macrophages virology, RNA Interference, RNA, Small Interfering administration & dosage, RNA, Small Interfering genetics, Receptors, CCR5 metabolism, beta Karyopherins antagonists & inhibitors, beta Karyopherins biosynthesis, beta Karyopherins genetics, Aptamers, Nucleotide administration & dosage, HIV Infections drug therapy, HIV-1 drug effects, Macrophages drug effects, Receptors, CCR5 genetics, SELEX Aptamer Technique methods
- 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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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