Virology is in a sense both one of the most important precursors and one of the most significant beneficiaries of structural and cellular molecular biology. Numerous breakthroughs in our understanding of the molecular interactions of viruses with host cells are ready for translation into medically important applications such as the prevention and treatment of viral infections. This book collects a wide variety of examples of frontline research into molecular aspects of viral infections from virological, immunological, cell- and molecular-biological, structural, and theoretical perspectives. - Contributors are world leaders in their fields of study and represent prestigious academic and research institutions- Review articles vary vastly in scope: some focus on a narrowly defined scientific problem of one particular virus with careful introduction for the non-specialist; others are essays in general and comparative virology with forays into specific viral species or molecules- The different perspectives complement each other and collectively the contributions provide an impression of the fast-moving frontlines of virology while showing how the problems have evolved- Structural data are presented through high-quality illustrations
Front Cover 1
The Molecular Basis of Viral Infection 4
Copyright 5
Contents 6
Contributors 12
Preface 16
References 20
Chapter 1: Unity in Diversity: Shared Mechanism of Entry Among Paramyxoviruses 22
1. Introduction to Paramyxoviruses 23
1.1. Classification and medical significance 23
1.2. Structure 26
1.3. Viral entry and life cycle 27
2. Structure and Function of the Paramyxovirus Glycoproteins 29
2.1. The receptor-binding protein 29
2.2. The fusion protein 31
3. Proposed Mechanisms of Receptor-Binding Protein and Fusion Protein Interactions 34
3.1. The globular heads of the receptor-binding protein selectively engage specific cellular receptors 34
3.2. The stalk domain of the receptor-binding protein interacts with and activates F 35
3.3. The role of the receptor-binding protein before receptor engagement 36
3.4. The receptor-binding protein transmits a triggering signal to the fusion protein upon receptor engagement 38
3.5. The fusion protein inserts its hydrophobic fusion peptide into the target membrane leading to the formation of the f... 40
3.6. The interaction between HN/H/G and F modulates infection in the natural host 42
4. Conclusions 43
Acknowledgments 44
References 44
Chapter 2: Alphavirus Entry into Host Cells 54
1. Introduction 55
1.1. Alphaviruses 55
1.2. Alphavirus life cycle 55
1.3. Alphavirus structure 56
2. Alphavirus Interaction with Host Cells 57
2.1. Role of attachment factors and receptors 58
2.1.1. Putative receptors 58
2.2. Routes for enveloped virus internalization 59
2.2.1. Endocytic routes 59
2.2.2. Nonendocytic routes 61
2.3. Conformational changes during entry 61
3. Measuring Viral Entry 62
3.1. Direct observations by electron microscopy 63
3.2. Role of membrane models in studies of virus entry 64
3.3. Role of inhibitors in studies of virus entry 65
4. Alphavirus Genome Delivery 66
4.1. Role of membrane fusion 66
4.2. Role of low pH 67
4.3. Role of pores in the cell membrane 68
5. Alphavirus Entry in the Absence of Membrane Fusion 68
5.1. A direct assay for entry at the plasma membrane 68
5.2. The role of temperature in the process of infection 70
5.3. The role time in the process of infection 73
5.4. The role of membrane potential 74
5.5. Similarities with other viruses 75
5.6. Implications of a new model for entry 76
6. Challenges and Perspectives 78
Acknowledgments 78
References 78
Chapter 3: The Mechanism of HCV Entry into Host Cells 84
1. Introduction 85
2. The Viral Particle Organization and Composition: A Fundamental Key to Decrypt Virus Entry 86
3. Early Steps of Virus Entry 89
3.1. Viral particle capture 89
3.1.1. The heparan sulfate proteoglycans 90
3.1.2. The LDL-r 91
3.1.3. The scavenger receptor B-I 92
3.2. Early particle rearrangements 92
4. Receptor Binding and Clustering 93
4.1. E1E2 glycoproteins: Viral mediator of particle binding 93
4.1.1. Heterodimerization 94
4.1.2. Glycosylation 94
4.1.3. Envelope glycoproteins and virus morphogenesis 95
4.1.4. Structure 96
4.1.5. E2 functions during virus binding 97
4.1.6. From the role of E1 to the importance of E1E2 dialogs 98
4.2. E2-CD81 binding engagement 99
4.2.1. CD81: A critical HCV receptor 99
4.2.2. CD81 as a major determinant for HCV-restricted species tropism 100
4.3. CD81-induced signaling and diffusion of receptor complexes 100
4.3.1. Epidermal growth factor-dependent signaling 100
4.3.2. EWI-2wint 101
4.4. A critical role of tight junction proteins 101
4.4.1. Claudin-1 102
4.4.2. Occludin 103
5. Postbinding Steps and Virus Fusion 104
5.1. Endocytosis and internalization 104
5.1.1. Endocytosis 104
5.1.2. The transferrin receptor: A role to be defined 105
5.2. Cell-to-cell transmission 105
5.3. Membrane fusion 106
5.3.1. Particle fusion-dependent rearrangements 108
5.3.1.1. Early membrane fusion-dependent rearrangements 108
5.3.1.2. Postattachment membrane fusion-dependent rearrangements 109
5.3.1.3. Late membrane fusion-dependent rearrangements 109
5.3.2. The mechanism of HCV fusion 110
5.3.2.1. The class of fusion protein 110
5.3.2.2. The HCV fusion protein: An unusual suspect 111
5.3.2.3. A model for HCV fusion 115
6. Concluding Remarks 115
Acknowledgments 118
References 118
Chapter 4: The Evolution of HIV-1 Interactions with Coreceptors and Mannose C-Type Lectin Receptors 130
1. Introduction 131
2. Chemokine Receptors as Critical HIV-1 Coreceptors 131
3. Evolution of Coreceptor Use During Virus Transmission and Establishment in the New Host 133
4. Intrapatient Evolution of HIV-1 Coreceptor Use 135
5. The Switch Pathway 135
6. The CCR5-Restricted Pathway 138
7. CLRs in HIV-1 Infection 140
8. CLRs and HIV-1 Interactions During Virus Transmission 143
9. CLRs and HIV-1 Interactions During the Chronic Infection Phase 145
10. Clinical Aspects of Virus Evolution at the Interface of Coreceptors and Mannose CLR 147
Acknowledgments 149
References 149
Chapter 5: A Game of Numbers: The Stoichiometry of Antibody-Mediated Neutralization of Flavivirus Infection 162
1. Introduction 163
2. Flavivirus Structure 165
3. A Multiple-Hit Model for the Neutralization of Flaviviruses 167
3.1. A neutralization-resistant population of flaviviruses 168
3.2. ADE of flavivirus infection 170
4. The Stoichiometry of Neutralization and Enhancement of Flaviviruses 171
4.1. The relationship between antibody occupancy and neutralization 171
4.2. Estimating the stoichiometry of WNV neutralization using mixed virion particles 172
4.3. Is 30 antibodies a reasonable number? 173
4.4. Experimental and conceptual limitations 173
5. Factors That Modulate the Stoichiometry of Neutralization 175
5.1. Virion maturation 176
5.2. The structural dynamics of virions 177
5.3. Complement 179
6. The Stoichiometry of ADE 180
7. Insights into Vaccines and Therapeutics 181
Acknowledgments 181
References 182
Chapter 6: TRIM21-Dependent Intracellular Antibody Neutralization of Virus Infection 188
1. Introduction 189
2. The Tripartite Motif Family 190
3. TRIM21 is a High-Affinity Cytosolic Fc Receptor 191
4. TRIM21 Mediates Antibody-Dependent Intracellular Neutralization 192
5. TRIM21 is a Sensor for Cytoplasmic Antibody 194
6. TRIM21 Functions are Ubiquitin Dependent 194
7. In Vivo Relevance 195
8. Viral Determinants of TRIM21-Mediated Neutralization 196
9. TRIM21 Exerts Highly Efficient Incremental Neutralization 198
10. The Persistent Fraction 201
11. Comparison of TRIM21 with TRIM5a 201
12. Conclusions 204
Acknowledgments 204
References 204
Chapter 7: Picornavirus-Host Interactions to Construct Viral Secretory Membranes 210
1. Back on the Radar 211
2. Getting to 3A 211
3. GBF1 213
4. PI4KB 214
5. ACBD3 216
6. Cholesterol 219
7. 2B-2C Pore Forming With ER-Golgi Membranes 220
8. Next Steps 221
8.1. Leveraging genomics 221
8.2. Proteomic screening 222
8.3. Complex biochemistry 223
9. Conclusion 225
Acknowledgments 226
References 226
Chapter 8: Retroviral Factors Promoting Infectivity 234
1. Introduction 235
1.1. Retrovirus infection and retrovirus infectivity 235
1.1.1. Different modalities of retrovirus infection 235
1.1.2. The infection process 236
1.2. Retrovirus infectivity: What we mean and how we measure it 237
1.3. How do retroviral auxiliary factors promote infectivity? 238
2. Retroviral Auxiliary Factors that Promote Infectivity 240
2.1. Promoting infectivity by facilitating nuclear entry 240
2.1.1. Vpr 240
2.2. Promoting infectivity by protecting the stability of the retroviral genome during reverse transcription 241
2.2.1. Retroviral dUTPases 241
2.2.2. Does Vpr promote infectivity by affecting reverse transcription and incorporation of dUTP? 241
2.2.3. Vpx and the counteraction of SAMHD1 242
2.3. Protecting the retroviral genome from deamination 244
2.3.1. Vif 244
2.3.2. Bet 246
2.3.3. GlycoGag 247
2.4. Promoting infectivity by preserving Env function on virion particles 248
2.4.1. Vpu, Nef, ORF-A 248
3. Retrovirus Factors that Promote Virion Infectivity with a Yet Unknown Mechanism: The Nef and glycoGag Enigma 249
3.1. Nef 249
3.1.1. The protein and its multifunctional activity 249
3.1.2. The mechanistic details of the Nef effect on infectivity 251
3.1.3. Why is the infectivity of Nef-negative particles defective? 251
3.1.4. What is the nature of the modification of the virus particle promoted by Nef which accounts for the effect on infe... 253
3.1.5. Is Nef functioning as a virion protein? 253
3.1.6. Does Nef affect incorporation or functionality of other retroviral proteins? 254
3.1.7. Does Nef affect virion incorporation of cell-derived components? 254
3.2. Nef is not alone: glycoGag 255
3.2.1. How do Nef-like factors promote retrovirus infection? 257
3.3. Are there other Nef-like factors promoting retrovirus infectivity? 258
4. Final Remarks 258
References 259
Chapter 9: The Cytoplasmic Tail of Retroviral Envelope Glycoproteins 274
1. Introduction 275
2. Retroviral Assembly 279
3. Synthesis and Function of Env 280
4. Function of the Retroviral Env CT 282
4.1. Anterograde trafficking 282
4.2. Retrograde trafficking 283
4.3. Env packaging into particles 284
4.4. Signaling 286
4.5. Role of the CT of retroviral TM proteins in regulating Env conformation 288
4.6. Role of Gag and virion maturation in regulating Env function 289
4.7. HIV-1 versus SIV gp41 CT 290
4.8. Role of Env in counteracting BST-2 291
4.9. Env CT as a therapeutic target? 292
5. Conclusions 292
Acknowledgments 293
References 293
Chapter 10: Molecular Determinants of the Ratio of Inert to Infectious Virus Particles 306
1. Introduction: A Wide Range of Particle-to-Infectious-Unit Ratio 307
2. Infectious or Infecting? 308
3. Defective from the Start 316
4. Decay in Suspension 328
5. Abortive Infection 330
5.1. Abortive fates at the cell surface 330
5.2. Intracellular routes to abortive infection 333
6. Conclusions 336
Acknowledgment 338
References 338
Chapter 11: The Role of Chance in Primate Lentiviral Infectivity: From Protomer to Host Organism 348
1. Introduction 348
2. Host Entry 350
2.1. Modeling acquisition 350
2.2. Modeling initial viral replication and establishment 353
3. Cell Entry 356
3.1. Infecting a cell 356
3.1.1. Cell factors influencing viral entry and cell infection 359
3.2. Preventing the infection of a cell: The role of neutralizing antibodies 360
3.2.1. Analogies in antiviral drug treatment 364
4. Synthesis and Outlook 364
Acknowledgments 366
References 367
Chapter 12: Virus-Encoded 7 Transmembrane Receptors 374
1. Evolutionary Context of v7TMRs 375
2. Functional Divergence from Cellular Chemokine Receptors 383
2.1. Ligand specificity-Broadened repertoire/lack of (known) ligands 383
2.2. Constitutive signaling activity 387
2.3. Constitutive endocytosis 389
2.4. Homo- and heterodimerization of v7TMRs 390
3. Biological Roles of Viral CKRs 392
3.1. Oncogenesis, angiogenesis, and vascular disease 392
3.1.1. Beta 27/28 and 33 395
3.1.2. Gamma 74 397
3.1.3. Gamma BILF1 398
3.2. Tissue-specific tropism and virus persistence/latency 399
3.2.1. Beta 27/28 399
3.2.2. Beta 33 400
3.2.3. Beta 78 401
3.2.4. Gamma 74 402
4. Concluding Remarks 403
References 403
Chapter 13: EBV, the Human Host, and the 7TM Receptors: Defense or Offense? 416
1. EBV Infection 417
1.1. Viral infection, entry, and tropism 417
1.2. Lytic replication 419
1.3. Latent infection 420
1.4. Regulation of latency, replication, and virus reactivation 422
2. Immune Response and Immune Evasion 423
3. EBV-BILF1-A Virus-Encoded 7TM Receptor with Immune Evasive Functions 425
3.1. Immune evasion strategy of EBV-BILF1 425
3.2. Signaling and tumorigenesis of EBV BILF1 427
4. EBI2: An Endogenous 7TM Receptor Manipulated by EBV 428
4.1. A family of oxysterols acts as ligands for the EBI2 receptor 428
4.2. Roles of the EBI2-oxysterol axis in the immune response 430
4.3. A potential role for the EBI2-oxysterol axis in EBV infection 431
5. Manipulation of the Host Immune System 7TM Receptors and Ligands by EBV-The Chemokine System 432
6. EBV-Associated Diseases 435
6.1. Infectious mononucleosis 435
6.2. Diseases in immunocompetent patients 438
6.3. Diseases in immunocompromised patients 438
7. Drug-Target Potential 439
8. Conclusions 440
Acknowledgment 440
References 440
Index 450
Color Plates 459
Preface
P.J. Klasse, Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, USA
True, in a single conversation with someone we can discern particular traits. But it is only through repeated encounters in varied circumstances that we can recognize these traits as characteristic and essential. For a writer, for a musician, or for a painter, this variation of circumstances that enables us to discern, by a sort of experimentation, the permanent features of character is found in the variety of the works themselves.
From Marcel Proust's preface to John Ruskin's The Bible of Amiens.
The Ebola River, a tributary to the Congo, flows north of the village of Yambuku. There, in 1976, hundreds of people rapidly succumbed to a lethal hemorrhagic fever. The cause, Ebola virus, is a member of the genus Filoviridae, comprising single-stranded negative-RNA viruses with the idiosyncratic filamentous or worm-like morphology that has given them their name.1 As a tragic Ebola epidemic now rages in West Africa, killing thousands, efforts to find a cure and a vaccine will intensify. It is already striking how the advancing field of filovirus studies shares questions and problems with the investigations—some old and established, some rapidly evolving—of other viruses, as exemplified in this book. Thus, knowledge is developing of how filoviruses enter cells,2 the identity of the receptors for the virus on susceptible cells,3,4 which cellular genes these viruses activate, how that activation affects the innate immune responses and pathogenesis,5,6 how the virus is neutralized by antibodies, and which antibodies protect against infection.7–10
Thomas Milton Rivers, working at The Rockefeller Institute, which I see through the window when composing this Preface, established virology as a discipline separate from bacteriology.11 He perspicaciously stated: “Viruses appear to be obligate parasites in the sense that their reproduction is dependent on living cells.” His anthology Filterable Viruses (Baltimore: Williams and Wilkins, 1928) covered everything worth knowing about viruses at the time. Today, when the number of PubMed entries in virology is around a million, an anthology in general virology must be considerably less comprehensive. The current collection encompasses a number of topical forays into molecular aspects of viral replication and coexistence with host organisms. The chapters in this anthology offer rich opportunities to compare how specific questions are answered for different viruses. As with the example of Ebola virus above, certain themes recur and the emerging patterns of similarities and differences may provoke new questions and stimulate collaborations among virologists with distinct specialties.
Their eclectic diversity notwithstanding, the chapters form a narrative of sorts, first adhering kairologically to the replicative cycle that viruses largely share, and then broadening to depict wider aspects of virus–host interactions. Thus, the first three chapters depict entry into susceptible cells by different viruses: paramyxoviruses (Chapter “Unity in Diversity: Shared Mechanism of Entry Among Paramyxoviruses,” Palgen et al.), alphavirus (Chapter “Alphavirus Entry into Host Cells,” Vancini et al.), and hepatitis C virus (Chapter “The Mechanism of HCV Entry into Host Cells,” Douam et al.). Entry requires viral interactions with specific receptors, as delineated in these chapters. Enveloped viruses can potentially enter either by fusing at the cell surface or by first following one of several distinct endocytic routes and then fusing with the endocytic vesicle. The exact mechanisms have been hotly debated for many viruses and these chapters bring new clarity and perhaps some surprises.
Then we shift the scope somewhat and consider the evolution of the entry mediator of HIV, viz., its envelope glycoprotein, Env. Now Env is extremely variable and capable of modulating its interactions with various host molecules: with mannose C-type lectins, which are possibly involved in attachment and transmission, and with the main receptor for the virus, CD4, as well as with the obligate coreceptors, which the virus fastidiously picks among a subset of the seven-transmembrane chemokine receptors. The strengths of the receptor interactions evolve concomitantly with the selection pressure that waxes and wanes as the virus escapes from the coevolving specificities of neutralizing antibodies and gets transmitted to immunologically naïve host organisms (Chapter “The Evolution of HIV Interactions with Coreceptors and Mannose C-Type Lectin Receptors,” Borggren and Jansson).
Having obliquely touched on neutralization, we then narrow the focus to what is probably the quantitatively best understood example of how antibodies block viral infectivity, i.e., neutralization of flaviviruses: in Chapter “A Game of Numbers: The Stoichiometry of Antibody-Mediated Neutralization of Flavivirus Infection,” Pierson and Diamond analyze the fine stoichiometric details of neutralizing antibody binding to flavivirions and explain why the same antibodies can either neutralize or enhance infectivity depending on what numbers bind to the virion.
We continue the theme of neutralization but switch to the naked adenoviruses, common causes of gastroenteritis, conjunctivitis, otitis, and respiratory tract infections. In Chapter “TRIM21-Dependent Intracellular Antibody Neutralization of Virus Infection,” McEwan and James describe the groundbreaking discovery that the cytoplasmic factor TRIM21 joins antibodies to effect cytoplasmic neutralization of adenovirus. TRIM21 might also augment the antibody-mediated neutralization of other naked viruses. That cytoplasmic neutralization occurs has long been suggested, even for enveloped viruses, but without decisive evidence; such claims have sometimes been erroneously linked to the kinetics and stoichiometry of neutralization.12 But the newly discovered definitive mechanism, which depends on the traversal of antibody–capsid complexes into the cytoplasm, has its own distinct quantitative implications.
We then extend the consideration of postentry events to later steps in the replicative cycle, including viral assembly and release. The first example is how picornaviruses, although they as naked viruses lack membranes in their virions, interact with intracellular membranes and highjack components of the secretory pathway for their replication (Chapter “Picornavirus–Host Interactions to Construct Viral Secretory Membranes,” Greninger). The story then returns to enveloped viruses in the form of retroviruses and the extensive cast of auxiliary factors they have evolved to counteract cellular barriers to their replication (Chapter “Retroviral Factors Promoting Infectivity,” Cuccurullo et al.). Thereafter, the tale turns to the cytoplasmic domains of the retroviral Env proteins (Chapter “The Cytoplasmic Tail of Retroviral Envelope Glycoproteins,” Tedbury and Freed). These cytoplasmic and intravirional tails are particularly long among the lentiviruses, to which HIV belongs. They contain motifs for endocytosis and trafficking of the Env proteins; they even exert transmembraneous conformational effects on the outer Env, the target for neutralizing antibodies. Toward the end of the replicative cycle, when Env gets incorporated into the viral envelope, these tails juxtapose the internal Gag precursor that drives the budding of virions from the cell surface. Furthermore, when retroviruses and other enveloped viruses assemble and egress, they usurp multiple cellular factors, evincing quintessential parasitism.
The scene is then set for some analyses of the free virus particles themselves. First, the classic virological measurement of inert-to-infective particle ratio is examined in general and for particular viruses (Chapter “Molecular determinants of the ratio of inert to infectious virus particles,” Klasse). Then, taking the primate lentiviruses, which include HIV, as examples, Regoes and Magnus quantitatively dissect the contributions of individual Env subunits to the function of Env trimers, and of trimers to virion infectivity. These insights segue into analyses of the probabilities that inocula containing certain infectious doses establish infection in the host organism (Chapter “The Role of Chance in Primate Lentiviral Infectivity: From Protomer to Host Organism”).
The ascent from the molecular determinants of individual virion infectivity up to the establishment of infection at the level of a host organism, thus crowning the accounts of the progression through the viral replicative cycle at the cellular level, finally ushers in the topic of virus–host coexistence. Viruses often cause disease. Their interactions with the innate and adaptive immune systems modulate their pathogenesis. Host and virus have evolved together, sometimes for a long time. Herpesviruses may have diverged into the three families alpha-, beta-, and gammaherpesvirinae 180–220 million years ago, cospeciations among mammals having continued during the past 80 million years.13 In spite of those time lapses, herpesviruses can still get on our nerves (as when herpes simplex virus survives in the ganglion Gasseri or Varicella-Zoster virus gives facial palsy). Although far from perfect, the host's adaptation to these longtime companions is...
| Erscheint lt. Verlag | 13.1.2015 |
|---|---|
| Sprache | englisch |
| Themenwelt | Naturwissenschaften ► Biologie ► Biochemie |
| Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie | |
| Naturwissenschaften ► Biologie ► Mikrobiologie / Immunologie | |
| Naturwissenschaften ► Biologie ► Ökologie / Naturschutz | |
| Naturwissenschaften ► Physik / Astronomie ► Angewandte Physik | |
| Technik | |
| ISBN-10 | 0-12-802587-5 / 0128025875 |
| ISBN-13 | 978-0-12-802587-1 / 9780128025871 |
| Haben Sie eine Frage zum Produkt? |
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