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      Cell-specific RNA aptamer against human CCR5 specifically targets HIV-1 susceptible cells and inhibits HIV-1 infectivity.

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          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.

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          Author and article information

          Journal
          Chem. Biol.
          Chemistry & biology
          1879-1301
          1074-5521
          Mar 19 2015
          : 22
          : 3
          Affiliations
          [1 ] Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
          [2 ] Division of Comparative Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
          [3 ] HIV Pathogenesis Research Laboratory, Antiviral Gene Therapy Research Unit, Department of Molecular Medicine and Haematology, School of Pathology, University of the Witwatersrand, Parktown 2193, South Africa; Department of Molecular and Experimental Medicine (MEM-115), The Scripps Research Institute, La Jolla, CA 92037, USA.
          [4 ] Department of Molecular and Experimental Medicine (MEM-115), The Scripps Research Institute, La Jolla, CA 92037, USA; Biotechnology and Biomedical Sciences, The University of New South Wales, Sydney, NSW 2052, Australia.
          [5 ] Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. Electronic address: jrossi@coh.org.
          Article
          S1074-5521(15)00037-X NIHMS662235
          10.1016/j.chembiol.2015.01.005
          25754473
          3a738975-79b9-4003-a677-cfd91c5ea4e6
          Copyright © 2015 Elsevier Ltd. All rights reserved.
          History

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