Inhibition of the human chemokine receptor CXCR4 by antisense phosphorothioate oligodeoxyribonucleotides

The CXC chemokine receptor CXCR4/fusion, a major coreceptor for the T-cell line T-tropic (X4) HIV-1 virus, plays a critical role in T-tropic virus fus ion and entry into permissive cells. In the present study we describe the e ffects of an antisense phosphorothioate oligodeoxyribonucleotide (anti-S-OD N) on the inhibition of CXCR4 gene expression in X4 HIV-1 infected HeLa-CD4 cells, to find more efficacious therapeutic possibilities for human immuno deficiency virus type 1 (HIV-1) infection. The naked antisense phosphorothi oate oligodeoxyribonucleotide (anti-S-ODN-1), containing the AUG initiation codon at the center of the oligodeoxyribonucleotide, showed a slightly hig her inhibitory effect on HIV-1 gag p24 production among all sequences teste d. We also examined the concomitant use of a basic peptide transfection rea gent, nucleosomal histone proteins (RNP), for the delivery of the anti-S-OD N-1. The anti-S-ODN-1 encapsulated with RNP had higher inhibitory effects o n p24 products than the naked anti-S-ODN-1. When the anti-S-ODN-1 encapsula ted with RNP was incubated with HeLa-CD4 cells, the surface levels of this chemokine receptor showed high suppression, indicating sequence-specific in hibition. The activities of unmodified oligodeoxyribonucleotide are effecti vely enhanced by using a basic peptide, RNP. (C) 2001 Federation of Europea n Biochemical Societies. Published by Elsevier Science B.V. All rights rese rved.