Enhanced antisense inhibition of human immunodeficiency virus type 1 in cell cultures by DLS delivery system.
The relatively poor cell uptake of oligonucleotides and subsequent transport to the cytoplasm and nucleus is the main limitation in antisense therapeutics. The use of lipid-based carrier system is one of the most promising approaches to overcome these problems. In this study, we report the use of a new lipidic formulation to deliver a phosphorothioate oligonucleotide antisense directed against the regulatory gene rev of the HIV-1 genome and its application to the inhibition of HIV-1 in different cell culture models. Antiviral activity of either DLS-complexed or non-complexed oligonucleotides (ODNs) was compared in acutely and chronically infected cells. We have demonstrated that substantial antisense activity could be achieved at subnanomolar concentrations with DLS-complexed ODN in both acute and chronic infection systems. DLS-association highly improved inhibitory activity of the antisense ODN in acutely infected Molt-3 cells (100-fold) and primary cells (1000-fold) and in chronically infected H9 cells (1,500,000-fold). We have shown that anti-HIV activity of phosphorothioate ODNs can be strongly enhanced by using the DLS carrier system.
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Département de Microbiologie et Immunologie, Faculté de Médecine, Université de Montréal, Québec, Canada. carole.lavigne@sympatico.ca
Thierry
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D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D015757:Genes, rev; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008081:Liposomes; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D004337:Drug Carriers; D008081:Liposomes; D016376:Oligonucleotides, Antisense