Biological Response Modifiers - Interferons, Double-Stranded RNA and 2',5'-Oligoadenylates

Introduction.- 2 Intracellular Antiviral Defence Mechanisms: 2-5A/RNase L and p68 Kinase Pathways.- 3 Alterations in the Level of 2-5A.- 3.1 Cultured Cells.- 3.2 HIV Patients.- 4 Activation of the 2-5A System and p68 Kinase by dsRNA.- 4.1 Activation of 2-5OAS by hnRNA.- 4.2 Activation of 2-5OAS by the TAR Sequence of HIV-1-LTR.- 4.3 Activation of p68 Kinase by the TAR Sequence of HIV-1-LTR.- 5 Modulation of Intracellular Antiviral Mechanisms by dsRNA Analogues.- 5.1 Poly (I) · Poly (C12U) (Ampligen): Chemistry and Physical Properties.- 5.2 Modulation of Cytokine Action and Natural Killer Cell Activity.- 5.3 Anti-HIV Activity.- 5.4 Activation of 2-5OAS.- 5.5 Modulation of p68 Kinase Activity.- 5.6 Inhibition of DNA Topoisomerase I.- 5.7 Degradation by dsRNase.- 6 Mechanism of the Antiviral Effect.- 6.1 Binding to Cell Surface Receptors.- 6.2 Binding to 2-5OAS and p68 Kinase.- 6.3 Activation of 2-5OAS.- 7 Antiproliferative Activity of dsRNA.- 8 Mechanism of the Antiproliferative Effect of Poly (I) · Poly (C12U).- 9 Clinical Experience.- 9.1 AIDS.- 9.2 Chronic Fatigue Syndrome.- 9.3 Cancer.- 10 Drug-Resistant HIV.- 11 Combination with Other Anti-HIV Compounds.- 11.1 AZT.- 11.2 dsRNA Intercalating Agents.- 12 Perspectives.- References.- The Antiviral Activity of RNA-Dye Combinations.- 1 Introduction.- 2 The Structure of Double-Stranded RNA.- 3 Structural Consequences of Intercalation.- 4 Antiviral Activity of Intercalative Dyes.- 5 Antiviral Activity of Anthraquinones.- 6 Antiviral Activity of Xanthenes.- 7 Toxicity of Dye/RNA Combinations.- 8 Dye/RNA Combinations and HIV-1.- 9Interferon Induction and Direct Viral Inactivation of Dye/RNA Combinations.- 10 Subcellular Localization of Dyes and Dye/RNA Combinations.- 11 Dye-Induced Condensation of RNA.- 12 Biological Consequences of Dye/RNA Combinations.- 13 Summary.- References.- Chemical Synthesis of 2?5?-Oligoadenylate Analogues.- 1 Introduction.- 2 Biochemical Mechanism of Interferon Activity.- 3 The 2-5-OligoA System.- 4 2?,5?-Oligoadenylate Degradation by Phosphodiesterase.- 5 Chemically Synthesized Structural Analogues of 2?,5?-Oligonucleotide.- 5.1 Modification at the Sugar Moiety.- 5.2 Modification of the Aglycon in 2-5A Analogues.- 5.3 Modification of the Internucleotidic Bonds in 2?,5?-Oligoadenylates.- 5.4 2?,5?-Oligoadenylate Conjugates.- References.- Homologies Between Different Forms of 2-5A Synthetases.- 1 Introduction.- 2 Primary Structure of the Rat 2-5A Synthetase cDNA.- 3 Amino Acid Sequence of Rat 2-5A Synthetase.- 4 Comparison with Other Sequences of 2-5 A Synthetases.- 5 Summary.- References.- 2-5A and Virus Infection.- 1 Introduction.- 2 Antiviral Action of Interferon.- 3 Antiviral Function of the 2-5A/RNase L System.- 3.1 Virus Infection and the 2-5A/RNase L System.- 3.2 Antiviral Activity of 2-5A Molecules.- 3.3 Antiviral Activity of Core 2-5A.- 3.4 Other Utilizations of Natural 2-5A Analogues.- 4 The Fluctuation of the 2-5A/RNase L System.- 4.1 Persistent Infection.- 4.2 Acute Infection.- 5 Conclusions.- References.- The 2-5A System and HIV Infection.- 1 Immunodeficient State in HIV Infection.- 2 The 2-5A Pathway.- 3 2-5A Metabolism in HIV-1-Infected Cells.- 4 Modulation of 2-5OA/RNase L Activity by HIV-1 RNA and Protein.- 4.1 Tat-TAR Interaction.- 4.2 Activation of 2-5OAS by HIV TAR.- 4.3 Interaction of HIV TAR with p68 Protein Kinase.- 5Modulation of Intracellular Antiviral Mechanisms by 2-5A Analogues.- 5.1 Cordycepin Analogues.- 5.2 Phosphorothioate Analogues.- 5.3 Cellular Uptake of 2-5A Analogues.- 6 Inhibition of Reverse Transcriptase by 2-5A Analogues.- 7 Inhibition of DNA Topoisomerase I by 2-5A.- 7.1 Alterations of DNA Topoisomerase Activities in HIV-Infected Cells.- 7.2 Cellular Topoisomerase I.- 7.3 HIV-Associated Topoisomerase I.- 7.4 Mechanism of Action.- 8 Stimulation of 2-5A Metabolism by Lectins.- 9 "Intracellular Immunization" of Cells with HIV-LTR-2-5OAS Hybrid DNA.- 10 Summary.- References.- 2?5?-Oligoadenylate Synthetase in Autoimmune BB Rats.- 1 Introduction.- 2 Development of Diabetes in BB Rats Is Affected by Viruses.- 3 Effects of dsRNA in BB Rats.- 4 The Poly I:C Effect on Lymphocyte Subgroups.- 5 Concepts and Hypotheses.- References.- Oligoadenylate and Cyclic AMP: Interrelation and Mutual Regulation.- 1 Introduction.- 2 Interaction of 2-5A and cAMP: Direct Regulation of the Enzymes of cAMP and 2-5A Metabolism.- 2.1 2-5A-Dependent Activation of Phosphodiesterase of cAMP.- 2.2 cAMP-Dependent Induction of 2-5A Synthetase.- 2.3 Putative Mechanism of the cAMP-Dependent Induction of 2-5A Synthetase.- 2.4 cAMP-Dependent Phosphorylation of the Inhibitor of 2?-PDE. Inhibition of 2?-PDE.- 3 Interferons and cAMP.- 3.1 Involvement of cAMP in the Interferon-Dependent Regulation of the 2-5A System.- 3.2 The Cyclic AMP/2-5A System Mimics Partially the Antiviral Activity of IFNs.- 4 Cyclic AMP-Dependent Phosphorylation Causes the Elevation of the 2-5A Level Correlating with Antiproliferative Effects.- 5 Summary.- References.- Regulation of HIV Replication in Monocytes by Interferon.- 1 Introduction.- 1.1 CD4+ T-cells, the HIV-Infected Cell in Blood.- 1.2 Macrophages, theHIV-Infected Cell in Tissue 222 1.2.1 HIV Infection of Monocytes in Culture.- 1.3 Changes in the Cytokine Network During HIV Infection.- 2 Interferons and HIV Infection.- 2.1 Identification of the Key Issues.- 2.1.1 What Induces IFN-?.- 2.1.2 What Is the Best Time for IFN-? Antiviral Activity?.- 2.2 IFN-? Antiviral Activity in T-Cells.- 2.2.1 Effects of IFN-? at the Time of Initial HIVInfection.- 2.2.2 A Defect in HIV Assembly?.- 2.3 IFN-? Antiviral Activity in Monocytes.- 2.3.1 Effects of IFN-? at the Time of InitialHIV Infection.- 2.3.2 Effects of IFN-? on Established ProductiveHIV Infection.- 2.3.2.1 The Window of Opportunity.- 2.4 IFN-?-Induced Antiviral Pathways inHIV-Infected Monocytes.- 2.5 IFN-?-Induced Latency in HIV-InfectedMonocytes.- 2.6 Transcriptional Mechanisms for IFN-?-Induced Antiviral Activity.- 2.6.1 At the LTR - Are NF-? B and Spl the Culprits?.- 2.6.2 At the LTR and Beyond - Tat and Rev.- 2.6.3 A Model for IFN-? Action?.- 3 Conclusion and Future Directions.- References.- Transmembrane Signaling by IFN-?.- 1 Introduction.- 1.1 Background.- 1.2 Transcriptional Activation by IFN-? and the Role of DNA-Binding Factors.- 1.3 Multisubunit Structure of the IFN-? Receptors.- 2 The Roles of PKC and PTK in Transmembrane Signaling by IFN-?.- 2.1 Signal Transduction by Polypeptide Ligands.- 2.2 The Role of DAG and PKC in IFN-? Signaling.- 2.2.1 Rapid changes in Lipid Hydrolysis and DAG in IFN-? Signaling.- 2.2.2 IFN-? and Activation of PKC.- 2.2.3 Involvement of PKC in Posttranscriptional Effects of IFN-?.- 2.3 The Role of Tyrosine Phosphorylation and PTK in IFN-? Signaling.- 2.3.1 Complementation with the TYK2 PTK.- 2.3.2 Tyrosine Phosphorylation of ISGF3? and ISG Transcriptional Activation.- 2.3.3 Rapid Tyrosine Phosphorylation inResponse to IFN-?.- 2.4 Specificity of Signaling for Different Ligands.- 2.5 Analogies of Transmembrane Signaling Through the IFN-? Receptor with That of Other Receptors.- 3 Conclusions.- References.- Photolabeling of the Enzymes of the 2-5A Synthetase/RNase L/p68 Kinase Antiviral Systems with Azido Probes.- 1 Introduction.- 2 Photoaffinity Labeling of the ATP Binding Domain of 2-5A Synthetase by 2- and 8-AzidoATP.- 3 Photoaffinity Labeling of RNase L and 2-5A Binding Proteins by 2- and 8-Azido 2?,5?-Adenylate Photoprobes.- 4 Photoaffinity Labeling of the dsRNA Binding Domain of 2-5A Synthetase by Azido dsRNAs.- 5 Photoaffinity Labeling of HIV-1 Reverse Transcriptase.- References.