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 fusion and entry into permissive cells. In the present study, we describe the effects of an antisense phosphorothioate oligodeoxyribonucleotide (anti-S-ODN) on the inhibition of CXCR4 gene expression in X4 HIV-1 infected HeLa-CD4 cells, to find more efficacious therapeutic possibilities for human immunodeficiency virus type 1 (HIV-1) infection. The naked antisense phosphorothioate oligodeoxyribonucleotide (anti-S-ODN-1), containing the AUG initiation codon at the center of the oligodeoxyribonucleotide, showed a slightly higher inhibitory effect on HIV-1 gag p24 production among all sequences tested. We also examined the concomitant use of a basic peptide transfection reagent, nucleosomal histone proteins (RNP), for the delivery of the anti-S-ODN-1. The anti-S-ODN-1 encapsulated with RNP had higher inhibitory effects on p24 products than the naked anti-S-ODN-1. When the anti-S-ODN-1 encapsulated with RNP was incubated with HeLa-CD4 cells, the surface levels of this chemokine receptor showed high suppression, indicating sequence-specific inhibition. The activities of unmodified oligodeoxyribonucleotide are effectively enhanced by using a basic peptide, RNP.
Kusunoki
A
A
Department of Industrial Chemistry, Chiba Institute of Technology, Narashino, Chiba, Japan.
Saitou
T
T
Miyano-Kurosaki
N
N
Takaku
H
H
D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D018387:Codon, Initiator / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects*; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics* / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D013379:Substrate Specificity; D014162:Transfection
D015704:CD4 Antigens; D018387:Codon, Initiator; D016655:HIV Core Protein p24; D016376:Oligonucleotides, Antisense; D019718:Receptors, CXCR4; D016650:Fluorescein-5-isothiocyanate