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In vitro and in vivo cleavage of HIV-1 RNA by new SOFA-HDV ribozymes and their potential to inhibit viral replication.
Lainé, Sébastien; Scarborough, Robert J; Lévesque, Dominique; Didierlaurent, Ludovic; Soye, Kaitlin J; Mougel, Marylène; Perreault, Jean-Pierre; Gatignol, Anne.
Afiliação
  • Lainé S; Virus-Cell Interactions Laboratory, Lady Davis Institute for Medical Research, McGill University, Montréal, Canada.
RNA Biol ; 8(2): 343-53, 2011.
Article em En | MEDLINE | ID: mdl-21422817
ABSTRACT
RNA-based compounds are promising agents to inactivate viruses. New specific hepatitis delta virus (HDV)-derived ribozymes are natural molecules that can be engineered to specifically target a viral RNA. We have designed specific on-off adaptor (SOFA)-HDV ribozymes targeting the tat and rev sequences of the human immunodeficiency virus type 1 (HIV-1) RNA. We show that the SOFA-HDV ribozymes cleave their RNA target in vitro. They inhibit the Tat-mediated transactivation of HIV-1 from 62% to 86% in different assays. In vivo, the amount of HIV RNA was decreased by 60 and 86% with two distinct ribozymes, which indicates that the inhibition of HIV production is directly correlated to the decline in spliced and unspliced viral RNAs. These SOFAHDV- ribozymes inhibited the expression and the viral production of four HIV-1 strains, indicating an extended potential to act on multiple HIV variants. In HEK 293T and HeLa cells transfected with pNL4-3 and the SOFA-HDV-ribozymes, the reduced RNA levels consequently decreased the Gag protein expression in the cell and virus production in the supernatant. When transfected before HIV-1 infection, the ribozymes prevented the incoming virus from being expressed. The ribozymes inhibited HIV production up to 90% when transfected in combination with the HIV protease inhibitor Atazanavir. Our results strongly suggest that SOFA-HDV ribozymes have a great potential to target HIV-1 and to be used as therapeutic agents in combination therapy.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Replicação Viral / RNA Viral / RNA Catalítico / HIV-1 Limite: Humans Idioma: En Revista: RNA Biol Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2011 Tipo de documento: Article País de afiliação: Canadá
Buscar no Google
Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Replicação Viral / RNA Viral / RNA Catalítico / HIV-1 Limite: Humans Idioma: En Revista: RNA Biol Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2011 Tipo de documento: Article País de afiliação: Canadá