title: Cell-specific RNA aptamer against human CCR5 specifically targets HIV-1 susceptible cells and inhibits HIV-1 infectivity.
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.
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Jiehua
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Satheesan
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Haitang
authors.initials: H
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Weinberg
authors.affiliation: 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.
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Morris
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Burnett
authors.affiliation: 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.
authors.forename: John J
authors.initials: JJ
authors.lastname: Rossi
mesh_terms: D052157:Aptamers, Nucleotide / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000821:virology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D019713:Receptors, CCR5 / Q000235:genetics* / Q000378:metabolism; D052156:SELEX Aptamer Technique / Q000379:methods*; D028961:beta Karyopherins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D052157:Aptamers, Nucleotide; D034741:RNA, Small Interfering; D019713:Receptors, CCR5; C546476:TNPO3 protein, human; D028961:beta Karyopherins