Locked nucleic acid containing antisense oligonucleotides enhance inhibition of HIV-1 genome dimerization and inhibit virus replication |
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Authors: | Elmén Joacim Zhang Hong-Yan Zuber Bartek Ljungberg Karl Wahren Britta Wahlestedt Claes Liang Zicai |
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Affiliation: | Center for Genomics and Bioinformatics, Karolinska Institutet, Berzeliusv?g 35, 171 77 Stockholm, Sweden. joacim.elmen@cgb.ki.se |
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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. |
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Keywords: | LNA Antisense RNase H HIV Dimerization initiation site |
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