title: RNAi in combination with a ribozyme and TAR decoy for treatment of HIV infection in hematopoietic cell gene therapy.
abstract: Combinatorial therapies for the treatment of HIV infection have changed the course of the AIDS epidemic in developed nations where the antiviral drug combinations are readily available. Despite this progress, there are many problems associated with chemotherapy for AIDS including toxicities and emergence of viral mutants resistant to the drugs. Our goal has been the development of a hematopoietic gene therapy treatment for HIV infection. Like chemotherapy, gene therapy for treatment of HIV infection should be used combinatorially. We have thus combined three different inhibitory genes for treatment of HIV infection into a single lentiviral vector backbone. The inhibitory agents engage RNAi via a short hairpin RNA targeting HIV tat/rev mRNAs, a nucleolar localizing decoy that binds and sequesters the HIV Tat protein, and a ribozyme that cleaves and downregulates the CCR5 chemokine receptor used by HIV for cellular entry. This triple combination has proven to be highly effective for inhibiting HIV replication in primary hematopoietic cells, and is currently on track for human clinical application.
authors.affiliation: Division of Molecular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Li
authors.forename: Haitang
authors.initials: H
authors.lastname: Li
authors.forename: John J
authors.initials: JJ
authors.lastname: Rossi
mesh_terms: D065100:CCR5 Receptor Antagonists; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D015694:Gene Products, rev / Q000037:antagonists & inhibitors; D015696:Gene Products, tat / Q000037:antagonists & inhibitors; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006678:HIV / Q000187:drug effects; D015658:HIV Infections / Q000628:therapy*; D016325:HIV Long Terminal Repeat / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D016337:RNA, Catalytic / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000008:administration & dosage; D016896:Treatment Outcome; D054321:rev Gene Products, Human Immunodeficiency Virus; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D065100:CCR5 Receptor Antagonists; D015694:Gene Products, rev; D015696:Gene Products, tat; D016337:RNA, Catalytic; D034741:RNA, Small Interfering; D054321:rev Gene Products, Human Immunodeficiency Virus; C514860:rev protein, Human Immunodeficiency Virus-1; D054322:tat Gene Products, Human Immunodeficiency Virus