Locked nucleic acid containing antisense oligonucleotides enhance inhibition of HIV-1 genome dimerization and inhibit virus replication.
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.
Elmén
Joacim
J
Center for Genomics and Bioinformatics, Karolinska Institutet, Berzeliusväg 35, 171 77 Stockholm, Sweden. joacim.elmen@cgb.ki.se
Zhang
Hong-Yan
HY
Zuber
Bartek
B
Ljungberg
Karl
K
Wahren
Britta
B
Wahlestedt
Claes
C
Liang
Zicai
Z
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*
D016376:Oligonucleotides, Antisense; D016914:Ribonuclease H