title: Locked nucleic acid containing antisense oligonucleotides enhance inhibition of HIV-1 genome dimerization and inhibit virus replication.
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.
authors.affiliation: Center for Genomics and Bioinformatics, Karolinska Institutet, Berzeliusväg 35, 171 77 Stockholm, Sweden. joacim.elmen@cgb.ki.se
authors.forename: Joacim
authors.initials: J
authors.lastname: Elmén
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Zhang
authors.forename: Bartek
authors.initials: B
authors.lastname: Zuber
authors.forename: Karl
authors.initials: K
authors.lastname: Ljungberg
authors.forename: Britta
authors.initials: B
authors.lastname: Wahren
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
authors.forename: Zicai
authors.initials: Z
authors.lastname: Liang
mesh_terms: D019281:Dimerization; D004789:Enzyme Activation; D016679:Genome, Viral; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D019169:Jurkat Cells; D016376:Oligonucleotides, Antisense / Q000737:chemistry* / Q000494:pharmacology*; D016914:Ribonuclease H / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D016376:Oligonucleotides, Antisense; D016914:Ribonuclease H