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

Biological response modifiers are increasingly used in viral and cancer therapy. Since alterations of the immune system are the primary symptoms of HIV infection, especially therapies directed towards the modulation of the immune response have been under intense evaluation. This volume summarizes current knowledge of the interferon-based natural antiviral protection system including 2',5'-oligoadenylate and double-stranded RNA. It will also help to develop further a solid scientific rationale for the practical use of heterologous immunomodulators in the clinics.

Activation of the dsRNA-Dependent Kinase.- 1 Introduction.- 2 Mechanism of Activation of the dsRNA-Dependent Kinase.- 3 Regulation of the dsRNA-Dependent Kinase.- 4 Biological Significance of the dsRNA-Dependent Kinase.- 5 Conclusion and Prospective.- References.- Double-Stranded RNAs as Gene Activators.- 1 Introduction.- 2 Double-Stranded RNA as Gene Inducers.- 3 Interaction of dsRNA with Target Cells.- 4 dsRNAs as Gene Activators.- 5 Conclusions.- References.- Viral-Dependent Phosphorylation of a dsRNA-Dependent Kinase.- 1 Introduction.- 2 Plant-Virus Interactions.- 3 Plant-Protein Phosphorylation.- 4 Detection of Viral-Induced Phosphorylation.- 5 Characterization of Viral-Induced Phosphorylation.- 5.1 Stimulatory Molecules.- 5.2 Temporal Pattern of Phosphorylation.- 5.3 In Vivo Phosphorylation of p68.- 5.4 Characterization of p68 Protein Kinase Activity.- 5.5 Immunological Similarity with the Human p68.- 5.6 Peptide Sequencing.- 5.7 Transgenic Plant Studies.- 6 Homology with Mammalian Kinases.- 7 Conclusions and Future Directions.- References.- Cellular Inhibitors of the Interferon-Induced, dsRNA-Activated Protein Kinase.- 1 Introduction.- 2 A Cellular Inhibitor of the P68 Kinase from Influenza Virus-Infected Cells.- 2.1 Downregulation of the P68 Kinase During Influenza Virus Infection.- 2.2 Purification and Characterization of a Cellular Inhibitor of the P68 Kinase from Influenza Virus-Infected Cells.- 2.3 Identification of the 58-kDa Protein and a Specific Anti-Inhibitory Activity in Uninfected MDBK Cells.- 2.4 Model of P68 Kinase Regulation.- 3 Degradation of the P68 Kinase by a Cellular Protease During Poliovirus Infection.- 4 A Cellular Inhibitor That Regulates the P68 Kinase in 3T3-F442 Fibroblasts.- 5 A Cellular Inhibitor of the P68 Kinase in Oncogenic ras-Transformed BALB Cells.- 6 A Cellular Inhibitor of the P68 Kinase in Human Amnion FL Cells.- 7 Conclusions and Future Directions.- References.- Mechanism of the Antiretroviral Effect of dsRNA.- 1 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.- 9 Interferon 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.- 5 Modulation 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, the HIV-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 in Response 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.