The Experts below are selected from a list of 480 Experts worldwide ranked by ideXlab platform
Sudhir Agrawal - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of an anti human immunodeficiency virus antisense Oligodeoxynucleotide Phosphorothioate gem 91 in hiv infected subjects
Clinical Pharmacology & Therapeutics, 1995Co-Authors: Ruiwen Zhang, Harout Shahinian, Girish Amin, Russell R Martin, Zhihong Lu, Zhiwei Jiang, Jamal Temsamani, Paul J. Schechter, Michael S. Saag, Sudhir AgrawalAbstract:Human pharmacokinetics of an antisense Oligodeoxynucleotide Phosphorothioate (GEM 91) developed as an anti—human immunodeficiency virus (HIV) agent was carried out in this study. 35S-Labeled GEM 91 was administered to six HIV-infected individuals by means of 2-hour intravenous infusions at a dose of 0.1 mg/kg. Plasma disappearance curves for GEM 91—derived radioactivity could be described by the sum of two exponentials, with half-life values of 0.18 ± 0.04 and 26.71 ± 1.67 hours. The radioactivity in plasma was further evaluated by polyacrylamide gel electrophoresis, showing the presence of both intact GEM 91 and lower molecular weight metabolites. Urinary excretion represented the major pathway of elimination, with 49.15% ± 6.80% of the administered dose excreted within 24 hours and 70.37% ± 6.72% over 96 hours after dosing. The radioactivity in urine was associated with lower molecular weight metabolites. No drug-related toxicity was observed. Clinical Pharmacology & Therapeutics (1995) 58, 44–53; doi: 10.1016/0009-9236(95)90071-3
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pharmacokinetics and tissue distribution in rats of an Oligodeoxynucleotide Phosphorothioate gem 91 developed as a therapeutic agent for human immunodeficiency virus type 1
Biochemical Pharmacology, 1995Co-Authors: Ruiwen Zhang, Zhiwei Jiang, Robert B. Diasio, Tiepu Liu, Wayne M Galbraith, Sudhir AgrawalAbstract:Abstract An antisense Oligodeoxynucleotide Phosphorothioate, namely gene expression modulator 91 (GEM 91), has been demonstrated to have significant anti-human immunodeficiency virus activity in various tissue culture models. The present study was undertaken to determine the pharmacokinetics and tissue distribution of GEM 91 in rats following i.v. bolus administration of 35 S-radiolabeled GEM 91. Plasma disappearance curves for GEM 91-derived radioactivity could be described by the sum of two exponentials, with half-lives (mean ± SEM) of 0.95 (± 0.07) and 47.57 (± 14.48) hr. Urinary excretion represented the major pathway of elimination of GEM 91, with 26.67 ± 6.46% (mean ± SD) of the administered dose excreted within 24 hr and 58.12 ± 4.36% over 240 hr after GEM 91 administration. Fecal excretion was a minor pathway of elimination of GEM 91 with 1.4 ± 0.62% (mean ± SD) of the administered dose excreted over 24 hr and 8.54 ± 0.64% over 240 hr. A wide tissue distribution of GEM 91 was observed. During the initial 30 min, the highest levels of tissue radioactivity were found in the kidney, liver, spleen, lungs, and heart. Radioactivity was retained over longer time periods in the kidneys, liver, heart, and intestine. Analyses of the extracted radioactivities from plasma, kidney, and liver by gel electrophoresis showed the presence of both intact GEM 91 and degradative products with smaller molecular weights. Radioactivity in urine was found to be degradative metabolites of GEM 91. Based on the experimental data, pharmacokinetic parameters for GEM 91 in each tissue and biological fluids were calculated using computer-based two-compartmental i.v. bolus or absorption models. This study is important not only in providing the basis for future studies of GEM 91 in humans, but also in understanding the pharmacology and toxicology of antisense Oligodeoxynucleotide Phosphorothioates, in general.
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antisense Oligodeoxynucleotide Phosphorothioate complementary to gag mrna blocks replication of human immunodeficiency virus type 1 in human peripheral blood cells
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Julianna Lisziewicz, Alain R Thierry, Paolo Lusso, Frank F Weichold, Robert C Gallo, Jinyan Tang, Sudhir AgrawalAbstract:Abstract Gene-expression modulator 91 (GEM91) is a 25-nt antisense Oligodeoxynucleotide Phosphorothioate complementary to the Gag mRNA of human immunodeficiency virus type 1 (HIV-1). Cellular uptake and intracellular distribution of GEM91 within cells suggest that this oligomer is readily available for antisense activity. GEM91 inhibited HIV-1 replication in a dose-dependent and sequence-specific manner. In a comparative study, 2 microM GEM91 was as effective as 5 microM 3'-azido-3'-deoxythymidine in blocking virus replication during the 28-day treatment of an HIV-1-infected T-cell line. GEM91 also completely inhibited (> 99%) the growth of three different HIV-1 isolates in primary lymphocytes and prevented the cytopathic effect of the virus in primary CD4+ T cells. Similarly, treatment with GEM91 for 3 weeks of HIV-1/BaL-infected primary macrophages blocked virus replication. Based on GEM91 anti-HIV-activity, safety, and pharmacokinetic profile in animals, a clinical trial was started using this compound as an antisense oligonucleotide drug for the treatment of the acquired immunodeficiency syndrome.
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A rapid method for quantitation of Oligodeoxynucleotide Phosphorothioates in biological fluids and tissues.
Analytical Biochemistry, 1993Co-Authors: Jamal Temsamani, Michael Kubert, Sudhir AgrawalAbstract:A sensitive and simple method for the quantitation of oligonucleotide Phosphorothioates in biological fluids and tissues is described. This method is based on the extraction of the oligonucleotide from the biological fluids and tissues and immobilization on a nylon membrane. The membrane-bound Oligodeoxynucleotide Phosphorothioate is then hybridized with labeled complementary oligonucleotide and exposed to X-ray film. The data on the film can be scanned and used to create a standard curve. The sensitivity of detection by the method described here will be useful to monitor the pharmacokinetics of oligonucleotides in bodily fluids and distribution in various tissues. The results indicate that the method is rapid and allows handling of a large number of samples at the same time.
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Method for Sequencing Synthetic Oligodeoxynucleotide Phosphorothioates
Analytical biochemistry, 1993Co-Authors: Jinyan Tang, Allysen Roskey, Sudhir AgrawalAbstract:Abstract Sequencing of Oligodeoxynucleotide Phosphorothioate by a modified Sanger method of sequencing is described. The procedure involves ligation of synthetic Oligodeoxynucleotide Phosphorothioate to an Oligodeoxynucleotide, referred to here as "helper oligonucleotide." The helper oligonucleotide has a region which is complementary to T7 primer. By using DNA polymerase and nucleoside triphosphate mixture, 5′-labeled T7 primer is extended onto ligated Oligodeoxynucleotide Phosphorothioate, which is then analyzed on gel electrophoresis.
Ruiwen Zhang - One of the best experts on this subject based on the ideXlab platform.
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in vivo stability disposition and metabolism of a hybrid oligonucleotide Phosphorothioate in rats
Biochemical Pharmacology, 1995Co-Authors: Ruiwen Zhang, Zhiwei Jiang, Hui Zhao, Xueshu Zhang, Robert B. Diasio, Ivan Habus, L U Zhihong, Radhakrishnan P. IyerAbstract:Oligodeoxynucleotide Phosphorothioates containing segments of 2′-O-methyloligoribo-nucleotide Phosphorothioates at both 3′- and 5′-ends (hybrid oligonucleotide) have been shown to be potent antisense agents. In the present study, in vivo biostability, disposition, and excretion of a 25-mer hybrid oligonucleotide were determined in rats after i.v. bolus administration of the 35S-labeled oligonucleotide at a dose of 30 mg/kg. The plasma disappearance curve for the hybrid oligonucleotide could be described by a two-compartmental model, with half-lives of 0.34 and 52.02 hr, respectively. The majority of the radioactivity in plasma was associated with the intact hybrid oligonucleotide. Urinary excretion represented the major pathway of elimination, with 21.98 ± 3.21% (mean ± SD) of the administered dose excreted within 24 hr and 38.13 ± 2.99% over 240 hr post-dosing. The majority of the radioactivity in urine was associated with the degradative products with lower molecular weights, but the intact form was also detected by HPLC analysis. Fecal excretion was a minor pathway of elimination with 2.34 ± 0.13% of the administered dose excreted over 24 hr and 6.74 ± 0.40% over 240 hr post-dosing. A wide tissue distribution of hybrid oligonucleotide was observed based on radioactivity levels, and analysis by HPLC showed that the majority of the radioactivity in tissues was associated with the intact hybrid oligonucleotide. Further analyses of the experimental data provided a comprehensive pharmacokinetic analysis of hybrid oligonucleotide in each tissue. Compared with a previously examined Oligodeoxynucleotide Phosphorothioate (GEM 91) that has a similar nucleotide sequence, the hybrid oligonucleotide had a shorter distribution half-life and a longer elimination half-life, based on the quantitation of radioactivity in plasma. Although it had a similar tissue distribution pattern compared with other oligonucleotide Phosphorothioates such as GEM 91, the hybrid oligonucleotide was more stable in vivo, which may be important in the development of antisense oligonucleotides as therapeutic agents.
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pharmacokinetics of an anti human immunodeficiency virus antisense Oligodeoxynucleotide Phosphorothioate gem 91 in hiv infected subjects
Clinical Pharmacology & Therapeutics, 1995Co-Authors: Ruiwen Zhang, Harout Shahinian, Girish Amin, Russell R Martin, Zhihong Lu, Zhiwei Jiang, Jamal Temsamani, Paul J. Schechter, Michael S. Saag, Sudhir AgrawalAbstract:Human pharmacokinetics of an antisense Oligodeoxynucleotide Phosphorothioate (GEM 91) developed as an anti—human immunodeficiency virus (HIV) agent was carried out in this study. 35S-Labeled GEM 91 was administered to six HIV-infected individuals by means of 2-hour intravenous infusions at a dose of 0.1 mg/kg. Plasma disappearance curves for GEM 91—derived radioactivity could be described by the sum of two exponentials, with half-life values of 0.18 ± 0.04 and 26.71 ± 1.67 hours. The radioactivity in plasma was further evaluated by polyacrylamide gel electrophoresis, showing the presence of both intact GEM 91 and lower molecular weight metabolites. Urinary excretion represented the major pathway of elimination, with 49.15% ± 6.80% of the administered dose excreted within 24 hours and 70.37% ± 6.72% over 96 hours after dosing. The radioactivity in urine was associated with lower molecular weight metabolites. No drug-related toxicity was observed. Clinical Pharmacology & Therapeutics (1995) 58, 44–53; doi: 10.1016/0009-9236(95)90071-3
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pharmacokinetics and tissue distribution in rats of an Oligodeoxynucleotide Phosphorothioate gem 91 developed as a therapeutic agent for human immunodeficiency virus type 1
Biochemical Pharmacology, 1995Co-Authors: Ruiwen Zhang, Zhiwei Jiang, Robert B. Diasio, Tiepu Liu, Wayne M Galbraith, Sudhir AgrawalAbstract:Abstract An antisense Oligodeoxynucleotide Phosphorothioate, namely gene expression modulator 91 (GEM 91), has been demonstrated to have significant anti-human immunodeficiency virus activity in various tissue culture models. The present study was undertaken to determine the pharmacokinetics and tissue distribution of GEM 91 in rats following i.v. bolus administration of 35 S-radiolabeled GEM 91. Plasma disappearance curves for GEM 91-derived radioactivity could be described by the sum of two exponentials, with half-lives (mean ± SEM) of 0.95 (± 0.07) and 47.57 (± 14.48) hr. Urinary excretion represented the major pathway of elimination of GEM 91, with 26.67 ± 6.46% (mean ± SD) of the administered dose excreted within 24 hr and 58.12 ± 4.36% over 240 hr after GEM 91 administration. Fecal excretion was a minor pathway of elimination of GEM 91 with 1.4 ± 0.62% (mean ± SD) of the administered dose excreted over 24 hr and 8.54 ± 0.64% over 240 hr. A wide tissue distribution of GEM 91 was observed. During the initial 30 min, the highest levels of tissue radioactivity were found in the kidney, liver, spleen, lungs, and heart. Radioactivity was retained over longer time periods in the kidneys, liver, heart, and intestine. Analyses of the extracted radioactivities from plasma, kidney, and liver by gel electrophoresis showed the presence of both intact GEM 91 and degradative products with smaller molecular weights. Radioactivity in urine was found to be degradative metabolites of GEM 91. Based on the experimental data, pharmacokinetic parameters for GEM 91 in each tissue and biological fluids were calculated using computer-based two-compartmental i.v. bolus or absorption models. This study is important not only in providing the basis for future studies of GEM 91 in humans, but also in understanding the pharmacology and toxicology of antisense Oligodeoxynucleotide Phosphorothioates, in general.
Zhiwei Jiang - One of the best experts on this subject based on the ideXlab platform.
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in vivo stability disposition and metabolism of a hybrid oligonucleotide Phosphorothioate in rats
Biochemical Pharmacology, 1995Co-Authors: Ruiwen Zhang, Zhiwei Jiang, Hui Zhao, Xueshu Zhang, Robert B. Diasio, Ivan Habus, L U Zhihong, Radhakrishnan P. IyerAbstract:Oligodeoxynucleotide Phosphorothioates containing segments of 2′-O-methyloligoribo-nucleotide Phosphorothioates at both 3′- and 5′-ends (hybrid oligonucleotide) have been shown to be potent antisense agents. In the present study, in vivo biostability, disposition, and excretion of a 25-mer hybrid oligonucleotide were determined in rats after i.v. bolus administration of the 35S-labeled oligonucleotide at a dose of 30 mg/kg. The plasma disappearance curve for the hybrid oligonucleotide could be described by a two-compartmental model, with half-lives of 0.34 and 52.02 hr, respectively. The majority of the radioactivity in plasma was associated with the intact hybrid oligonucleotide. Urinary excretion represented the major pathway of elimination, with 21.98 ± 3.21% (mean ± SD) of the administered dose excreted within 24 hr and 38.13 ± 2.99% over 240 hr post-dosing. The majority of the radioactivity in urine was associated with the degradative products with lower molecular weights, but the intact form was also detected by HPLC analysis. Fecal excretion was a minor pathway of elimination with 2.34 ± 0.13% of the administered dose excreted over 24 hr and 6.74 ± 0.40% over 240 hr post-dosing. A wide tissue distribution of hybrid oligonucleotide was observed based on radioactivity levels, and analysis by HPLC showed that the majority of the radioactivity in tissues was associated with the intact hybrid oligonucleotide. Further analyses of the experimental data provided a comprehensive pharmacokinetic analysis of hybrid oligonucleotide in each tissue. Compared with a previously examined Oligodeoxynucleotide Phosphorothioate (GEM 91) that has a similar nucleotide sequence, the hybrid oligonucleotide had a shorter distribution half-life and a longer elimination half-life, based on the quantitation of radioactivity in plasma. Although it had a similar tissue distribution pattern compared with other oligonucleotide Phosphorothioates such as GEM 91, the hybrid oligonucleotide was more stable in vivo, which may be important in the development of antisense oligonucleotides as therapeutic agents.
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pharmacokinetics of an anti human immunodeficiency virus antisense Oligodeoxynucleotide Phosphorothioate gem 91 in hiv infected subjects
Clinical Pharmacology & Therapeutics, 1995Co-Authors: Ruiwen Zhang, Harout Shahinian, Girish Amin, Russell R Martin, Zhihong Lu, Zhiwei Jiang, Jamal Temsamani, Paul J. Schechter, Michael S. Saag, Sudhir AgrawalAbstract:Human pharmacokinetics of an antisense Oligodeoxynucleotide Phosphorothioate (GEM 91) developed as an anti—human immunodeficiency virus (HIV) agent was carried out in this study. 35S-Labeled GEM 91 was administered to six HIV-infected individuals by means of 2-hour intravenous infusions at a dose of 0.1 mg/kg. Plasma disappearance curves for GEM 91—derived radioactivity could be described by the sum of two exponentials, with half-life values of 0.18 ± 0.04 and 26.71 ± 1.67 hours. The radioactivity in plasma was further evaluated by polyacrylamide gel electrophoresis, showing the presence of both intact GEM 91 and lower molecular weight metabolites. Urinary excretion represented the major pathway of elimination, with 49.15% ± 6.80% of the administered dose excreted within 24 hours and 70.37% ± 6.72% over 96 hours after dosing. The radioactivity in urine was associated with lower molecular weight metabolites. No drug-related toxicity was observed. Clinical Pharmacology & Therapeutics (1995) 58, 44–53; doi: 10.1016/0009-9236(95)90071-3
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pharmacokinetics and tissue distribution in rats of an Oligodeoxynucleotide Phosphorothioate gem 91 developed as a therapeutic agent for human immunodeficiency virus type 1
Biochemical Pharmacology, 1995Co-Authors: Ruiwen Zhang, Zhiwei Jiang, Robert B. Diasio, Tiepu Liu, Wayne M Galbraith, Sudhir AgrawalAbstract:Abstract An antisense Oligodeoxynucleotide Phosphorothioate, namely gene expression modulator 91 (GEM 91), has been demonstrated to have significant anti-human immunodeficiency virus activity in various tissue culture models. The present study was undertaken to determine the pharmacokinetics and tissue distribution of GEM 91 in rats following i.v. bolus administration of 35 S-radiolabeled GEM 91. Plasma disappearance curves for GEM 91-derived radioactivity could be described by the sum of two exponentials, with half-lives (mean ± SEM) of 0.95 (± 0.07) and 47.57 (± 14.48) hr. Urinary excretion represented the major pathway of elimination of GEM 91, with 26.67 ± 6.46% (mean ± SD) of the administered dose excreted within 24 hr and 58.12 ± 4.36% over 240 hr after GEM 91 administration. Fecal excretion was a minor pathway of elimination of GEM 91 with 1.4 ± 0.62% (mean ± SD) of the administered dose excreted over 24 hr and 8.54 ± 0.64% over 240 hr. A wide tissue distribution of GEM 91 was observed. During the initial 30 min, the highest levels of tissue radioactivity were found in the kidney, liver, spleen, lungs, and heart. Radioactivity was retained over longer time periods in the kidneys, liver, heart, and intestine. Analyses of the extracted radioactivities from plasma, kidney, and liver by gel electrophoresis showed the presence of both intact GEM 91 and degradative products with smaller molecular weights. Radioactivity in urine was found to be degradative metabolites of GEM 91. Based on the experimental data, pharmacokinetic parameters for GEM 91 in each tissue and biological fluids were calculated using computer-based two-compartmental i.v. bolus or absorption models. This study is important not only in providing the basis for future studies of GEM 91 in humans, but also in understanding the pharmacology and toxicology of antisense Oligodeoxynucleotide Phosphorothioates, in general.
Julianna Lisziewicz - One of the best experts on this subject based on the ideXlab platform.
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antisense Oligodeoxynucleotide Phosphorothioate complementary to gag mrna blocks replication of human immunodeficiency virus type 1 in human peripheral blood cells
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Julianna Lisziewicz, Alain R Thierry, Paolo Lusso, Frank F Weichold, Robert C Gallo, Jinyan Tang, Sudhir AgrawalAbstract:Abstract Gene-expression modulator 91 (GEM91) is a 25-nt antisense Oligodeoxynucleotide Phosphorothioate complementary to the Gag mRNA of human immunodeficiency virus type 1 (HIV-1). Cellular uptake and intracellular distribution of GEM91 within cells suggest that this oligomer is readily available for antisense activity. GEM91 inhibited HIV-1 replication in a dose-dependent and sequence-specific manner. In a comparative study, 2 microM GEM91 was as effective as 5 microM 3'-azido-3'-deoxythymidine in blocking virus replication during the 28-day treatment of an HIV-1-infected T-cell line. GEM91 also completely inhibited (> 99%) the growth of three different HIV-1 isolates in primary lymphocytes and prevented the cytopathic effect of the virus in primary CD4+ T cells. Similarly, treatment with GEM91 for 3 weeks of HIV-1/BaL-infected primary macrophages blocked virus replication. Based on GEM91 anti-HIV-activity, safety, and pharmacokinetic profile in animals, a clinical trial was started using this compound as an antisense oligonucleotide drug for the treatment of the acquired immunodeficiency syndrome.
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Phosphorothioate Analogs Directed against the Rev-Responsive Element
1993Co-Authors: Julianna Lisziewicz, Robert C Gallo, Daisy Sun, Gerald Zon, Simon Daefler, Flossie Wong Staal, Mary E. KlotmaniAbstract:The interaction between the Rev protein of human immunodeficiency virus type 1 and its highly structured and conserved RNA target, the Rev-responsive element, is required for virus replication. We demonstrate that antisense Oligodeoxynucleotide Phosphorothioate analogs directed against the Rev-responsive element effec-tively inhibit Rev activity, as well as human immunodeficiency virus type 1 replication, and are candidates for antiviral therapy. Human immunodeficiency virus type I (HIV-1), the caus-ative agent of AIDS (24, 58, 61), has a number of genes involved in the complex regulation of virus expression. The rev gene of HIV-1 encodes an essential nuclear regulatory protein that is required for the cytoplasmic accumulation and expres-sion of genomic RNA, unspliced mRNA coding for Gag and Pol, and singly spliced mRNA coding for Env, Vpu, Vpr, an
Robert C Gallo - One of the best experts on this subject based on the ideXlab platform.
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antisense Oligodeoxynucleotide Phosphorothioate complementary to gag mrna blocks replication of human immunodeficiency virus type 1 in human peripheral blood cells
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Julianna Lisziewicz, Alain R Thierry, Paolo Lusso, Frank F Weichold, Robert C Gallo, Jinyan Tang, Sudhir AgrawalAbstract:Abstract Gene-expression modulator 91 (GEM91) is a 25-nt antisense Oligodeoxynucleotide Phosphorothioate complementary to the Gag mRNA of human immunodeficiency virus type 1 (HIV-1). Cellular uptake and intracellular distribution of GEM91 within cells suggest that this oligomer is readily available for antisense activity. GEM91 inhibited HIV-1 replication in a dose-dependent and sequence-specific manner. In a comparative study, 2 microM GEM91 was as effective as 5 microM 3'-azido-3'-deoxythymidine in blocking virus replication during the 28-day treatment of an HIV-1-infected T-cell line. GEM91 also completely inhibited (> 99%) the growth of three different HIV-1 isolates in primary lymphocytes and prevented the cytopathic effect of the virus in primary CD4+ T cells. Similarly, treatment with GEM91 for 3 weeks of HIV-1/BaL-infected primary macrophages blocked virus replication. Based on GEM91 anti-HIV-activity, safety, and pharmacokinetic profile in animals, a clinical trial was started using this compound as an antisense oligonucleotide drug for the treatment of the acquired immunodeficiency syndrome.
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Phosphorothioate Analogs Directed against the Rev-Responsive Element
1993Co-Authors: Julianna Lisziewicz, Robert C Gallo, Daisy Sun, Gerald Zon, Simon Daefler, Flossie Wong Staal, Mary E. KlotmaniAbstract:The interaction between the Rev protein of human immunodeficiency virus type 1 and its highly structured and conserved RNA target, the Rev-responsive element, is required for virus replication. We demonstrate that antisense Oligodeoxynucleotide Phosphorothioate analogs directed against the Rev-responsive element effec-tively inhibit Rev activity, as well as human immunodeficiency virus type 1 replication, and are candidates for antiviral therapy. Human immunodeficiency virus type I (HIV-1), the caus-ative agent of AIDS (24, 58, 61), has a number of genes involved in the complex regulation of virus expression. The rev gene of HIV-1 encodes an essential nuclear regulatory protein that is required for the cytoplasmic accumulation and expres-sion of genomic RNA, unspliced mRNA coding for Gag and Pol, and singly spliced mRNA coding for Env, Vpu, Vpr, an
