Efficacy and mode of action of hammerhead and hairpin ribozymes against various HIV-1 target sites

Molecular Therapy : the Journal of the American Society of Gene Therapy
Graham HotchkissLars Ahrlund-Richter

Abstract

Ribozymes have been proposed as gene therapy agents against HIV-1, although many fundamental questions about their mechanism of action remain unclear. Few studies have compared directly the potential of different modified ribozyme species against a particular target. Here we compare the relative abilities of hammerhead (HhU5) and hairpin (HpU5) ribozymes directed against a well-studied target RNA that has therapeutic potential, located in the untranslated 5' region (U5), to inhibit HIV-1 replication. The two types of ribozymes showed similar antiviral efficacy after being stably transfected into HUT78 cells and subsequently challenged with HIV-1(SF2), but the HhU5 ribozyme showed faster cleavage kinetics when tested in a cell-free system. In the second part of this study, we examined whether different ribozymes were able to inhibit the integration of proviral DNA in infected HUT78 cells. We found that cell pools stably expressing HpU5 could limit the appearance of integrated provirus, indicating that they could inhibit the infecting viral RNA before reverse transcription. A preintegration effect was also found for cell pools expressing a ribozyme targeting the nef gene (HhNef) or a ribozyme targeting the LTR (HhLTR). However, n...Continue Reading

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Citations

Jan 7, 2009·Journal of Biochemistry·Agnieszka Fedoruk-WyszomirskaJan Barciszewski
Nov 13, 2014·Expert Opinion on Therapeutic Targets·Elena Herrera-Carrillo, Ben Berkhout
Jul 21, 2015·Viruses·Elena Herrera-Carrillo, Ben Berkhout
Apr 7, 2006·The Journal of Gene Medicine·Dorothee von LaerKlaus Hasselmann
Jul 26, 2015·The Biochemical Journal·Agnieszka Fedoruk-WyszomirskaJan Barciszewski
Feb 9, 2021·Computational and Structural Biotechnology Journal·Yeu-Yang TsengWei-Li Hsu

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