Inhibition of human immunodeficiency virus replication by antisense oligodeoxynucleotides.

Goodchild, John; Agrawal, Sudhir; Civeira, M.P.; Sarin, Prem S.; Sun, Daisy; Zamecnik, Paul C.

doi:10.1073/pnas.85.15.5507

Cited by 213 publications

(90 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In earlier reports, we demonstrated that replication of human immunodeficiency virus (HIV) could be inhibited by normal phosphodiester oligodeoxynucleotide sequences complementary to HIV RNA (4,8). However, relatively short half-lives of normal oligonucleotides (9) in serum and in cells due to the presence of nucleases, and possibly the low permeability of these charged molecules into normal cells, limit their potential usefulness in vivo.…”

mentioning

confidence: 99%

Inhibition of human immunodeficiency virus in early infected and chronically infected cells by antisense oligodeoxynucleotides and their phosphorothioate analogues.

Agrawal¹,

Ikeuchi²,

Sun³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

196

View full text Add to dashboard Cite

Antisense oligodeoxynucleotides, both the phosphorothioate analogues and unmodified oligomers of the same sequence, inhibit replication and expression of human immunodeficiency virus already growing in tissue cultures of MOLT-3 cells with much greater efficacy than do mismatched ("random") oligomers and homooligomers of the same length and with the same internucleotide modification. This preferential inhibitory effect is elicited in as short a time as 4-24 hr postinfection. Likewise, antisense oligomers exhibit greater inhibitory effects on human immunodeficiency virus in chronically infected cells than do mismatched oligomers and homooligomers. Phosphorothioate antisense oligomers are up to 100 times more potent than unmodified oligomers of the same sequence in these inhibitory assays. These results, in major respects, confirm and extend those recently published by Matsukura et al. [Matsukura, M., Zon, G., Shinozuka, K., Robert-Guroff, M., Shimada, T., Stein, C. A., Mitsuza, H., Wong-Staal, F., Cohen, J. S. & Broder, S. (1989) Proc. Nati. Acad. Sci. USA 86,[4244][4245][4246][4247][4248]. They also point out the importance of computer analysis of sequences thought to be random but that in reality contain significant areas of likely hybridization, either to the viral genome or to the complementary DNA strand synthesized from it. They thus reinforce the concept that specific base pairing is a crucial feature of oligonucleotide inhibition of human immunodeficiency virus.Antisense oligodeoxynucleotides and their analogues have been used as tools for inhibiting viral replication (1-3), for blocking splicing and translation of mRNA (4, 5), and for regulating specific gene expression (6, 7). It has been found that an oligonucleotide complementary to a segment of a viral genome or an mRNA derived therefrom may interfere with the expression of that genetic segment by hybridization competition (1,2).In earlier reports, we demonstrated that replication of human immunodeficiency virus (HIV) could be inhibited by normal phosphodiester oligodeoxynucleotide sequences complementary to HIV RNA (4, 8). However, relatively short half-lives of normal oligonucleotides (9) in serum and in cells due to the presence of nucleases, and possibly the low permeability of these charged molecules into normal cells, limit their potential usefulness in vivo. To overcome this limitation, we and others (10-15) have studied internucleotide phosphate backbone-modified oligonucleotides, such as methylphosphonates (3, 10) as well as phosphorothioates and various phosphoramidates (11,12), for their antiviral activities against HIV.Here we report both the inhibition of HIV replication and the effect on cell growth of MOLT-3 cells that have been infected just 24 or 48 hr before addition of oligomers and also the effect on MOLT-3 cells chronically infected with HIV that were mixed with uninfected cells in the presence of oligodeoxynucleotides and their phosphorothioate analogues. MATERIALS AND METHODSOligonucleotide Synthesis. Oligonucleotides we...

show abstract

mentioning

confidence: 99%

Inhibition of human immunodeficiency virus in early infected and chronically infected cells by antisense oligodeoxynucleotides and their phosphorothioate analogues.

Agrawal¹,

Ikeuchi²,

Sun³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

196

View full text Add to dashboard Cite

show abstract

“…Major applications of such technologies have been for knockdown of gene expression by targeting mRNA with antisense oligonucleotides (AOs) to either block gene translation or induce mRNA degradation (4). Application of antisense technologies for interference with gene splicing was first established for the correction of the mutated ␤-globin gene.…”

mentioning

confidence: 99%

Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles

Lü

Rabinowitz

Chen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

364

291

View full text Add to dashboard Cite

Antisense oligonucleotide-mediated alternative splicing has great potential for treatment of Duchenne muscular dystrophy (DMD) caused by mutations within nonessential regions of the dystrophin gene. We have recently shown in the dystrophic mdx mouse that exon 23, bearing a nonsense mutation, can be skipped after intramuscular injection of a specific 2 -O-methyl phosphorothioate antisense oligoribonucleotide (2OMeAO). This skipping created a shortened, but in-frame, transcript that is translated to produce near-normal levels of dystrophin expression. This expression, in turn, led to improved muscle function. However, because DMD affects muscles body-wide, effective treatment requires dystrophin induction ideally in all muscles. Here, we show that systemic delivery of specific 2OMeAOs, together with the triblock copolymer F127, induced dystrophin expression in all skeletal muscles but not in cardiac muscle of the mdx dystrophic mice. The highest dystrophin expression was detected in diaphragm, gastrocnemius, and intercostal muscles. Large numbers of fibers with near-normal level of dystrophin were observed in focal areas. Three injections of 2OMeAOs at weekly intervals enhanced the levels of dystrophin. Dystrophin mRNA lacking the targeted exon 23 remained detectable 2 weeks after injection. No evidence of tissue damage was detected after 2OMeAO and F127 treatment either by serum analysis or histological examination of liver, kidney, lung, and muscles. The simplicity and safety of the antisense protocol provide a realistic prospect for treatment of the majority of DMD mutations. We conclude that a significant therapeutic effect may be achieved by further optimization in dose and regime of administration of antisense oligonucleotide.exon skipping ͉ muscular dystrophy

show abstract

“…(23,25,26) Anti-sense molecules were shown by several groups to inhibit HIV-1 in vitro when targeted towards critical HIV-1 genes such as tat, rev, and integrase, but the need for large amounts for in vivo studies apart from the problems associated with stability contributed to their failure to enter the clinic. (27) 4. RNA interference (RNAi): A natural way of gene silencing Diseases, for which a foreign gene can be identified as the cause, such as in the case of viral infections, are potentially treatable by blocking its expression that will cripple the causative agent.…”

Section: Newer Approaches To Therapymentioning

confidence: 99%

Crippling of HIV at Multiple Stages with Recombinant Adeno-Associated Viral Mediated RNA Interference

Batchu¹,

Gruzdyn²,

Qazi³

et al. 2011

Recent Translational Research in HIV/AIDS

View full text Add to dashboard Cite

Inhibition of human immunodeficiency virus replication by antisense oligodeoxynucleotides.

Cited by 213 publications

References 35 publications

Inhibition of human immunodeficiency virus in early infected and chronically infected cells by antisense oligodeoxynucleotides and their phosphorothioate analogues.

Inhibition of human immunodeficiency virus in early infected and chronically infected cells by antisense oligodeoxynucleotides and their phosphorothioate analogues.

Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles

Crippling of HIV at Multiple Stages with Recombinant Adeno-Associated Viral Mediated RNA Interference

Contact Info

Product

Resources

About