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Locked nucleic acid containing antisense oligonucleotides enhance inhibition of HIV-1 genome dimerization and inhibit virus replication.

Identifieur interne : 000324 ( Ncbi/Merge ); précédent : 000323; suivant : 000325

Locked nucleic acid containing antisense oligonucleotides enhance inhibition of HIV-1 genome dimerization and inhibit virus replication.

Auteurs : Joacim Elmén [Suède] ; Hong-Yan Zhang ; Bartek Zuber ; Karl Ljungberg ; Britta Wahren ; Claes Wahlestedt ; Zicai Liang

Source :

RBID : pubmed:15589834

Descripteurs français

English descriptors

Abstract

We have evaluated antisense design and efficacy of locked nucleic acid (LNA) and DNA oligonucleotide (ON) mix-mers targeting the conserved HIV-1 dimerization initiation site (DIS). LNA is a high affinity nucleotide analog, nuclease resistant and elicits minimal toxicity. We show that inclusion of LNA bases in antisense ONs augments the interference of HIV-1 genome dimerization. We also demonstrate the concomitant RNase H activation by six consecutive DNA bases in an LNA/DNA mix-mer. We show ON uptake via receptor-mediated transfection of a human T-cell line in which the mix-mers subsequently inhibit replication of a clinical HIV-1 isolate. Thus, the technique of LNA/DNA mix-mer antisense ONs targeting the conserved HIV-1 DIS region may provide a strategy to prevent HIV-1 assembly in the clinic.

DOI: 10.1016/j.febslet.2004.11.015
PubMed: 15589834

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pubmed:15589834

Le document en format XML

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<term>Enzyme Activation</term>
<term>Genome, Viral</term>
<term>HIV-1 (drug effects)</term>
<term>HIV-1 (genetics)</term>
<term>HIV-1 (isolation & purification)</term>
<term>Humans</term>
<term>Jurkat Cells</term>
<term>Oligonucleotides, Antisense (chemistry)</term>
<term>Oligonucleotides, Antisense (pharmacology)</term>
<term>Ribonuclease H (metabolism)</term>
<term>T-Lymphocytes (drug effects)</term>
<term>T-Lymphocytes (metabolism)</term>
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<term>Activation enzymatique</term>
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<term>Dimérisation</term>
<term>Génome viral</term>
<term>Humains</term>
<term>Lymphocytes T ()</term>
<term>Lymphocytes T (métabolisme)</term>
<term>Oligonucléotides antisens ()</term>
<term>Oligonucléotides antisens (pharmacologie)</term>
<term>Ribonuclease H (métabolisme)</term>
<term>Réplication virale ()</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (génétique)</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (isolement et purification)</term>
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<term>HIV-1</term>
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<term>HIV-1</term>
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<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
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<div type="abstract" xml:lang="en">We have evaluated antisense design and efficacy of locked nucleic acid (LNA) and DNA oligonucleotide (ON) mix-mers targeting the conserved HIV-1 dimerization initiation site (DIS). LNA is a high affinity nucleotide analog, nuclease resistant and elicits minimal toxicity. We show that inclusion of LNA bases in antisense ONs augments the interference of HIV-1 genome dimerization. We also demonstrate the concomitant RNase H activation by six consecutive DNA bases in an LNA/DNA mix-mer. We show ON uptake via receptor-mediated transfection of a human T-cell line in which the mix-mers subsequently inhibit replication of a clinical HIV-1 isolate. Thus, the technique of LNA/DNA mix-mer antisense ONs targeting the conserved HIV-1 DIS region may provide a strategy to prevent HIV-1 assembly in the clinic.</div>
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