Cross-clade inhibition of HIV-1 replication and cytopathology by using RNase P-associated external guide sequences

Proceedings of the National Academy of Sciences of the United States of America
G KrausH Hnatyszyn

Abstract

RNase P complexes have been proposed as a novel RNA-based gene interference strategy to inhibit gene expression in human malignancies and infectious diseases. This approach is based on the sequence-specific design of an external guide sequence (EGS) RNA molecule that can specifically hybridize to almost any complementary target mRNA and facilitate its cleavage by the RNase P enzyme component. We designed a truncated RNase P-associated EGS molecule to specifically recognize the U5 region of HIV-1 mRNA and mediate cleavage of hybridized mRNA by the RNase P enzyme. Genes encoding for this U5-EGS (560) molecule, as well as a U5 EGS (560D) antisense control, were cloned into retroviral plasmids and transferred into a CD4(+) T cell line. Transfected cells were exposed to increasing concentrations of HIV-1 clinical isolates from clades A, B, C, and F. Heterogeneous cultures of CD4(+) T cells expressing the U5 EGS (560) molecule were observed to maintain CD4 levels, were devoid of cytopathology, and did not produce HIV p24 gag antigen through 30 days after exposure to all HIV-1 clades at a multiplicity of infection of 0.01. Identical cells expressing the U5 EGS (560D) antisense control molecule underwent a loss of CD4 expression, produ...Continue Reading

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Citations

Sep 6, 2003·Gene·Stephen M L Raj, Fenyong Liu
Oct 29, 2010·The Journal of Biological Chemistry·Xiaohong JiangFenyong Liu
May 17, 2003·American Journal of Pharmacogenomics : Genomics-related Research in Drug Development and Clinical Practice·David SteeleGarrett A Soukup
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