Gene Therapy for HIV and Chronic Infections (Advances in Experimental Medicine and Biology, 848)

This book centers on gene therapy and gene transfer approaches to prevent or treat chronic virus infections. The main focus is on the Big Three: human immunodeficiency virus (HIV-1), hepatitis B virus (HBV) and hepatitis C virus (HCV). Ample anti-HIV drugs are currently available in the clinic and the development of an effective combination therapy has dramatically improved the lifespan and quality of life of infected individuals. A similar trend can already be recognized for HBV and HCV: the development of multiple (directly acting) antiviral drugs and plans to control or even cure the infection. However, approaches that help prevent infection, or which provide long-lasting treatment (such as a cure) remain important goals. Immunization through gene transfer vehicles encoding immunogenic viral proteins shows promise in preventing infections with complex, highly variable, viruses such as HIV-1 or HCV. Gene therapy applications for virus infections have been discussed since the early 1990’s. Whereas a true cure seems difficult to achieve for HIV-1 due to its intrinsic property to deposit its genome into that of the host, such attempts may be within reach for HCV where spontaneous viral clearance occurs in a small percentage of the infected individuals. The prospect of original gene therapy approaches may provide alternative ways to reach the same endpoint by, for example, silencing of CCR5 expression post-transcriptionally. Many alternative antiviral strategies have been developed based on a variety of novel molecular methods: e.g. ribozymes. Some studies have progressed towards pre-clinical animal models and a few antiviral gene therapies have progressed towards clinical trials. This book provides an overview of this rapidly progressing field, while focusing on the interface of gene therapy and immunology/vaccinology. Preface 6 Contents 10 Contributors 12 About the Editors 16 Gene Therapies for Hepatitis C Virus 18 Introduction 19 Molecular Biology of HCV 20 Viral Life Cycle 22 Host Cell Entry 22 Replication, Assembly, and Release 23 Current HCV Treatment 26 Current Therapies 26 Gene Therapy Strategies for HCV Infection 27 The RNAi Mechanism 27 RNAi Delivery 27 Hepatocyte-Specific Promoter Elements 31 Potential Targets for RNAi Therapy 32 MiRNA Blocking with Antisense Technology 33 Combinations of RNAi and Other Antivirals 34 Concluding Remarks 35 References 35 Recent Advances in Use of Gene Therapy to Treat Hepatitis B Virus Infection 47 Hepatitis B Virus Epidemiology 47 HBV Biology 49 RNAi Against HBV 50 Targeting cccDNA Using Engineered Sequence-Specific DNA Binding Proteins 51 Disrupting the HBV cccDNA Minichromosome 56 Transcriptional Gene Silencing with rTALEs 57 Conclusions 59 References 60 U1 interference (U1i) for Antiviral Approaches 66 Introduction: U1 Structure and Function 67 U1 Interference (U1i) 69 U1snRNP as a Therapeutic Tool 70 Rules for U1i 71 U1i Specificity 72 Other U1ins 73 U1i Combination with RNAi 74 Antiviral Use of U1i 74 HIV-1 74 HBV 76 Conclusion 80 References 81 Gene Therapy Strategies to Block HIV-1 Replication by RNA Interference 85 Introduction on the RNAi Mechanism 85 RNAi: From Natural Mechanism to Therapeutic Approach 86 HIV-1 as RNAi Target 88 HIV-1 Escape 90 Targeting Cellular Cofactors 92 Combinatorial RNAi Approaches 93 Improved shRNAs and the Novel AgoshRNA Design 95 Vector Issues 96 Preclinical Efficacy Tests 97 Preclinical Safety Tests 100 The Humanized Mouse Model 100 Gene Therapy Strategies for HIV-AIDS 101 RNAi Against Other Chronic Infections 103 References 104 HIV and Ribozymes 110 Introduction 111 Design of Anti-HIV-1 Ribozymes 112 Anti HIV-1 Ribozyme Target Sites 112 Ribozyme Expression Strategies 117 Ribozyme–RNA Conjugates 121 Anti-HIV-1 Ribozymes in Clinical Trials 122 Conclusions/Perspectives 123 References 124 Editing CCR5: A Novel Approach to HIV Gene Therapy 130 Introduction 131 CCR5 as a Target for HIV Antiretroviral Therapy 131 Gene Editing with Designer Nucleases 134 Target Cells 136 Applying Designer Nucleases for HIV Gene Therapy 137 Concluding Remarks 139 References 139 Synthetic DNA Approach to Cytomegalovirus Vaccine/Immune Therapy 144 Introduction 144 Overt Danger: CMV Infection and Its Burden to Public Health 145 CMV Microinfection: The Silent Threat 146 Quest for a CMV Vaccine/Immune Therapy 147 CMV Immunology 148 Vaccine Target Selection 149 Glycoproteins M and N 150 Glycoprotein B 151 Glycoproteins H, L, O 151 The Road So Far: Vaccine Platforms Under Development 152 Viral Vaccines 152 Nonviral Vaccines 153 DNA Vaccines 153 Conclusion 155 References 156 Vector-Mediated Antibody Gene Transfer for Infectious Diseases 162 Introduction 162 Finding Potent Broadly Neutralizing Antibodies for HIV-1 163 Passive Immunization Strategies for HIV 164 Vector-Mediated Antibody Gene Transfer to Bypass Adaptive Immune System 165 Choosing the Right Gene Transfer Vector 166 Antibody Gene Transfer for an HIV-1 Vaccine 167 Antibody Gene Transfer for HIV-1 Therapy 169 Antibody Gene Transfer for Respiratory Tract Infections 171 Other Applications for Antibody Gene Transfer 173 Limitations of rAAV Gene Transfer 174 References 175 HIV Latency and the Noncoding RNA Therapeutic Landscape 181 Chronic HIV Infection and the Search for Novel Therapies 182 HIV Life Cycle 182 Viral Latency 184 HIV Self-Mediated Transcription Regulation 184 Noncoding RNAs and Gene Regulation 185 Noncoding RNAs Associated with HIV Infection 187 HIV-Derived Noncoding RNAs 188 Small Noncoding RNAs 188 MicroRNAs 188 Small Interfering RNAs 189 Long Noncoding RNAs 189 Host-Derived Noncoding RNAs 190 MicroRNAs 190 Long Noncoding RNAs 191 Noncoding RNA-Based and Therapeutic Targeting of HIV Latency 192 miRNA Antagonism 192 Small-RNA-Induced Transcriptional Gene Silencing of HIV 192 Small-RNA-Induced Transcriptional Activation of HIV 194 Conclusions 195 References 196 C Peptides as Entry Inhibitors for Gene Therapy 202 Introduction 203 The HIV-1 Entry Process 203 C Peptides as HIV-1 Fusion Inhibitors 205 Gene Therapy Approaches Involving C Peptides 206 C Peptides as Antiviral Genes 206 Membrane-Anchored C Peptides 207 Intracellular Immunization and Selective Survival Advantage 207 Membrane-Anchored C46 208 Secreted C Peptides 209 Target Cells and Gene Transfer Systems for C Peptides 210 Next-Generation C Peptides 211 Elongated C Peptides 213 C Peptides with HIV-2 and SIV Activity 213 C Peptides with Enhanced Helix Stability 213 C Peptides with Reduced Immunogenicity 214 C Peptide Gene Therapy in Nonhuman Primates 214 Clinical Trials 215 Conclusions and Outlook 217 References 218 Aptamer–siRNA Chimeras for HIV 221 HIV-1 221 Targeting HIV-1 by siRNAs 224 RNAi Mechanism 224 siRNAs Against HIV-1 226 Current siRNA Delivery Approaches for HIV-1 227 Targeting HIV-1 by Aptamer–siRNA Chimera 229 Aptamers Overview 229 Aptamers for HIV-1 230 Aptamer–siRNA Chimeras for HIV-1 232 Anti-gp120 Aptamer–siRNA 232 Anti-CD4 Aptamer–siRNA 235 Conclusion and Future Perspective 236 References 237 Index 245 This volume examines gene therapy and gene transfer approaches to preventing or treating chronic virus infections, focusing on the Big Three viral pathogens- HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV). It explores molecular antiviral strategies, including RNA interference, aptamer-siRNA chimeras, U1i interference, editing CCR5, alternative genetic vaccination by intramuscular gene transfers of virus vectors, and HIV latency in the context of non-coding RNA. This title is a volume of the American Society of Gene and Cell Therapy, a sub-series of the highly successful Advances in Experimental Medicine and Biology. In eleven illustrated chapters, leading international researchers contextualize the structure, operation, and impact of pathogens; examine the existing genetic and molecular research; and extract possible methods of preventing and treating chronic viral infections while evaluating the current body of knowledge. Authoritative and multifaceted, Gene Therapy for HIV and Chronic Infections is an ideal guide for researchers in the fields of gene therapy and immunology interested in expanding their knowledge on how to design an effective gene therapy against a viral pathogen Front Matter....Pages i-xvi Gene Therapies for Hepatitis C Virus....Pages 1-29 Recent Advances in Use of Gene Therapy to Treat Hepatitis B Virus Infection....Pages 31-49 U1 interference (U1i) for Antiviral Approaches....Pages 51-69 Gene Therapy Strategies to Block HIV-1 Replication by RNA Interference....Pages 71-95 HIV and Ribozymes....Pages 97-116 Editing CCR5 : A Novel Approach to HIV Gene Therapy....Pages 117-130 Synthetic DNA Approach to Cytomegalovirus Vaccine/Immune Therapy....Pages 131-148 Vector-Mediated Antibody Gene Transfer for Infectious Diseases....Pages 149-167 HIV Latency and the Noncoding RNA Therapeutic Landscape....Pages 169-189 C Peptides as Entry Inhibitors for Gene Therapy....Pages 191-209 Aptamer–siRNA Chimeras for HIV....Pages 211-234 Back Matter....Pages 235-236