Specific Inhibition of Human Immunodeficiency Virus Type 1 Replication by Antisense Oligonucleotides: An in vitro Model for Treatment

• Published in: Proceedings of the National Academy of Sciences - PNAS 1992-12, Vol.89 (23), p.11209-11213
• Main Authors: Lisziewicz, Julianna, Sun, Daisy, Klotman, Mary, Agrawal, Sudhir, Zamecnik, Paul, Gallo, Robert
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antisense oligonucleotides; Antiviral agents; Antivirals; Base Sequence; Biological and medical sciences; Cell Survival - drug effects; Cells, Cultured; Cellular biology; Chemotherapy; HIV; HIV 1; HIV-1 - genetics; HIV-1 - growth & development; Human immunodeficiency virus; human immunodeficiency virus 1; Humans; In Vitro Techniques; Infections; Medical research; Medical sciences; Molecular Sequence Data; Mutation; Oligomers; Oligonucleotides; Oligonucleotides, Antisense - chemistry; Oligonucleotides, Antisense - pharmacology; Pharmacology. Drug treatments; rev genes; Syncytia; Time Factors; Virus replication; Virus Replication - drug effects; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.89.23.11209

We have developed a culture system, simulating in vivo conditions of human immunodeficiency virus type 1 (HIV-1) infection, to evaluate the long-term efficacy of antisense oligonucleotide treatment. Five oligonucleotide phosphorothioates (28-mers), complementary to different regions of HIV-1 RNA, blocked replication of the virus in a sequence-specific manner at 1 μM concentration. Variations in antiviral activity were seen among the different oligonucleotides, revealing an effect of target selection. Mismatched or random oligonucleotide phosphorothioates delayed, but did not completely inhibit, HIV-1 replication. In the case of inhibition by a splice-acceptor-site antisense oligodeoxynucleotide, a break-through phenomenon occurred after 25 days of treatment, suggesting the development of an "escape mutant." This result did not occur when the inhibitory oligodeoxynucleotides were complementary to the primary-sequence areas of the rev-responsive element and rev-1 genes. Sequential treatment of HIV-1-infected cells with a combination of different antisense oligonucleotides, each administered once, also prevented the development of escape mutants. Our results suggest that chemotherapy based on specifically targeted antisense-oligonucleotide phosphorothioates may be an effective method for reducing the viral burden in HIV-1-infected individuals at clinically achievable oligonucleotide concentrations.