Klasse The Molecular Basis of Viral Infection

1. Auflage 2015
ISBN: 978-0-12-802587-1
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 129, 458 Seiten

Reihe: Progress in Molecular Biology and Translational Science

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

Autoren/Hrsg.

Klasse, P.J

Inhaltsverzeichnis

1;Front Cover;1
2;The Molecular Basis of Viral Infection;4
3;Copyright;5
4;Contents;6
5;Contributors;12
6;Preface;16
6.1;References;20
7;Chapter 1: Unity in Diversity: Shared Mechanism of Entry Among Paramyxoviruses;22
7.1;1. Introduction to Paramyxoviruses;23
7.1.1;1.1. Classification and medical significance;23
7.1.2;1.2. Structure;26
7.1.3;1.3. Viral entry and life cycle;27
7.2;2. Structure and Function of the Paramyxovirus Glycoproteins;29
7.2.1;2.1. The receptor-binding protein;29
7.2.2;2.2. The fusion protein;31
7.3;3. Proposed Mechanisms of Receptor-Binding Protein and Fusion Protein Interactions;34
7.3.1;3.1. The globular heads of the receptor-binding protein selectively engage specific cellular receptors;34
7.3.2;3.2. The stalk domain of the receptor-binding protein interacts with and activates F;35
7.3.3;3.3. The role of the receptor-binding protein before receptor engagement;36
7.3.4;3.4. The receptor-binding protein transmits a triggering signal to the fusion protein upon receptor engagement;38
7.3.5;3.5. The fusion protein inserts its hydrophobic fusion peptide into the target membrane leading to the formation of the f...;40
7.3.6;3.6. The interaction between HN/H/G and F modulates infection in the natural host;42
7.4;4. Conclusions;43
7.5;Acknowledgments;44
7.6;References;44
8;Chapter 2: Alphavirus Entry into Host Cells;54
8.1;1. Introduction;55
8.1.1;1.1. Alphaviruses;55
8.1.2;1.2. Alphavirus life cycle;55
8.1.3;1.3. Alphavirus structure;56
8.2;2. Alphavirus Interaction with Host Cells;57
8.2.1;2.1. Role of attachment factors and receptors;58
8.2.1.1;2.1.1. Putative receptors;58
8.2.2;2.2. Routes for enveloped virus internalization;59
8.2.2.1;2.2.1. Endocytic routes;59
8.2.2.2;2.2.2. Nonendocytic routes;61
8.2.3;2.3. Conformational changes during entry;61
8.3;3. Measuring Viral Entry;62
8.3.1;3.1. Direct observations by electron microscopy;63
8.3.2;3.2. Role of membrane models in studies of virus entry;64
8.3.3;3.3. Role of inhibitors in studies of virus entry;65
8.4;4. Alphavirus Genome Delivery;66
8.4.1;4.1. Role of membrane fusion;66
8.4.2;4.2. Role of low pH;67
8.4.3;4.3. Role of pores in the cell membrane;68
8.5;5. Alphavirus Entry in the Absence of Membrane Fusion;68
8.5.1;5.1. A direct assay for entry at the plasma membrane;68
8.5.2;5.2. The role of temperature in the process of infection;70
8.5.3;5.3. The role time in the process of infection;73
8.5.4;5.4. The role of membrane potential;74
8.5.5;5.5. Similarities with other viruses;75
8.5.6;5.6. Implications of a new model for entry;76
8.6;6. Challenges and Perspectives;78
8.7;Acknowledgments;78
8.8;References;78
9;Chapter 3: The Mechanism of HCV Entry into Host Cells;84
9.1;1. Introduction;85
9.2;2. The Viral Particle Organization and Composition: A Fundamental Key to Decrypt Virus Entry;86
9.3;3. Early Steps of Virus Entry;89
9.3.1;3.1. Viral particle capture;89
9.3.1.1;3.1.1. The heparan sulfate proteoglycans;90
9.3.1.2;3.1.2. The LDL-r;91
9.3.1.3;3.1.3. The scavenger receptor B-I;92
9.3.2;3.2. Early particle rearrangements;92
9.4;4. Receptor Binding and Clustering;93
9.4.1;4.1. E1E2 glycoproteins: Viral mediator of particle binding;93
9.4.1.1;4.1.1. Heterodimerization;94
9.4.1.2;4.1.2. Glycosylation;94
9.4.1.3;4.1.3. Envelope glycoproteins and virus morphogenesis;95
9.4.1.4;4.1.4. Structure;96
9.4.1.5;4.1.5. E2 functions during virus binding;97
9.4.1.6;4.1.6. From the role of E1 to the importance of E1E2 dialogs;98
9.4.2;4.2. E2-CD81 binding engagement;99
9.4.2.1;4.2.1. CD81: A critical HCV receptor;99
9.4.2.2;4.2.2. CD81 as a major determinant for HCV-restricted species tropism;100
9.4.3;4.3. CD81-induced signaling and diffusion of receptor complexes;100
9.4.3.1;4.3.1. Epidermal growth factor-dependent signaling;100
9.4.3.2;4.3.2. EWI-2wint;101
9.4.4;4.4. A critical role of tight junction proteins;101
9.4.4.1;4.4.1. Claudin-1;102
9.4.4.2;4.4.2. Occludin;103
9.5;5. Postbinding Steps and Virus Fusion;104
9.5.1;5.1. Endocytosis and internalization;104
9.5.1.1;5.1.1. Endocytosis;104
9.5.1.2;5.1.2. The transferrin receptor: A role to be defined;105
9.5.2;5.2. Cell-to-cell transmission;105
9.5.3;5.3. Membrane fusion;106
9.5.3.1;5.3.1. Particle fusion-dependent rearrangements;108
9.5.3.1.1;5.3.1.1. Early membrane fusion-dependent rearrangements;108
9.5.3.1.2;5.3.1.2. Postattachment membrane fusion-dependent rearrangements;109
9.5.3.1.3;5.3.1.3. Late membrane fusion-dependent rearrangements;109
9.5.3.2;5.3.2. The mechanism of HCV fusion;110
9.5.3.2.1;5.3.2.1. The class of fusion protein;110
9.5.3.2.2;5.3.2.2. The HCV fusion protein: An unusual suspect;111
9.5.3.2.3;5.3.2.3. A model for HCV fusion;115
9.6;6. Concluding Remarks;115
9.7;Acknowledgments;118
9.8;References;118
10;Chapter 4: The Evolution of HIV-1 Interactions with Coreceptors and Mannose C-Type Lectin Receptors;130
10.1;1. Introduction;131
10.2;2. Chemokine Receptors as Critical HIV-1 Coreceptors;131
10.3;3. Evolution of Coreceptor Use During Virus Transmission and Establishment in the New Host;133
10.4;4. Intrapatient Evolution of HIV-1 Coreceptor Use;135
10.5;5. The Switch Pathway;135
10.6;6. The CCR5-Restricted Pathway;138
10.7;7. CLRs in HIV-1 Infection;140
10.8;8. CLRs and HIV-1 Interactions During Virus Transmission;143
10.9;9. CLRs and HIV-1 Interactions During the Chronic Infection Phase;145
10.10;10. Clinical Aspects of Virus Evolution at the Interface of Coreceptors and Mannose CLR;147
10.11;Acknowledgments;149
10.12;References;149
11;Chapter 5: A Game of Numbers: The Stoichiometry of Antibody-Mediated Neutralization of Flavivirus Infection;162
11.1;1. Introduction;163
11.2;2. Flavivirus Structure;165
11.3;3. A Multiple-Hit Model for the Neutralization of Flaviviruses;167
11.3.1;3.1. A neutralization-resistant population of flaviviruses;168
11.3.2;3.2. ADE of flavivirus infection;170
11.4;4. The Stoichiometry of Neutralization and Enhancement of Flaviviruses;171
11.4.1;4.1. The relationship between antibody occupancy and neutralization;171
11.4.2;4.2. Estimating the stoichiometry of WNV neutralization using mixed virion particles;172
11.4.3;4.3. Is 30 antibodies a reasonable number?;173
11.4.4;4.4. Experimental and conceptual limitations;173
11.5;5. Factors That Modulate the Stoichiometry of Neutralization;175
11.5.1;5.1. Virion maturation;176
11.5.2;5.2. The structural dynamics of virions;177
11.5.3;5.3. Complement;179
11.6;6. The Stoichiometry of ADE;180
11.7;7. Insights into Vaccines and Therapeutics;181
11.8;Acknowledgments;181
11.9;References;182
12;Chapter 6: TRIM21-Dependent Intracellular Antibody Neutralization of Virus Infection;188
12.1;1. Introduction;189
12.2;2. The Tripartite Motif Family;190
12.3;3. TRIM21 is a High-Affinity Cytosolic Fc Receptor;191
12.4;4. TRIM21 Mediates Antibody-Dependent Intracellular Neutralization;192
12.5;5. TRIM21 is a Sensor for Cytoplasmic Antibody;194
12.6;6. TRIM21 Functions are Ubiquitin Dependent;194
12.7;7. In Vivo Relevance;195
12.8;8. Viral Determinants of TRIM21-Mediated Neutralization;196
12.9;9. TRIM21 Exerts Highly Efficient Incremental Neutralization;198
12.10;10. The Persistent Fraction;201
12.11;11. Comparison of TRIM21 with TRIM5a;201
12.12;12. Conclusions;204
12.13;Acknowledgments;204
12.14;References;204
13;Chapter 7: Picornavirus-Host Interactions to Construct Viral Secretory Membranes;210
13.1;1. Back on the Radar;211
13.2;2. Getting to 3A;211
13.3;3. GBF1;213
13.4;4. PI4KB;214
13.5;5. ACBD3;216
13.6;6. Cholesterol;219
13.7;7. 2B-2C Pore Forming With ER-Golgi Membranes;220
13.8;8. Next Steps;221
13.8.1;8.1. Leveraging genomics;221
13.8.2;8.2. Proteomic screening;222
13.8.3;8.3. Complex biochemistry;223
13.9;9. Conclusion;225
13.10;Acknowledgments;226
13.11;References;226
14;Chapter 8: Retroviral Factors Promoting Infectivity;234
14.1;1. Introduction;235
14.1.1;1.1. Retrovirus infection and retrovirus infectivity;235
14.1.1.1;1.1.1. Different modalities of retrovirus infection;235
14.1.1.2;1.1.2. The infection process;236
14.1.2;1.2. Retrovirus infectivity: What we mean and how we measure it;237
14.1.3;1.3. How do retroviral auxiliary factors promote infectivity?;238
14.2;2. Retroviral Auxiliary Factors that Promote Infectivity;240
14.2.1;2.1. Promoting infectivity by facilitating nuclear entry;240
14.2.1.1;2.1.1. Vpr;240
14.2.2;2.2. Promoting infectivity by protecting the stability of the retroviral genome during reverse transcription;241
14.2.2.1;2.2.1. Retroviral dUTPases;241
14.2.2.2;2.2.2. Does Vpr promote infectivity by affecting reverse transcription and incorporation of dUTP?;241
14.2.2.3;2.2.3. Vpx and the counteraction of SAMHD1;242
14.2.3;2.3. Protecting the retroviral genome from deamination;244
14.2.3.1;2.3.1. Vif;244
14.2.3.2;2.3.2. Bet;246
14.2.3.3;2.3.3. GlycoGag;247
14.2.4;2.4. Promoting infectivity by preserving Env function on virion particles;248
14.2.4.1;2.4.1. Vpu, Nef, ORF-A;248
14.3;3. Retrovirus Factors that Promote Virion Infectivity with a Yet Unknown Mechanism: The Nef and glycoGag Enigma;249
14.3.1;3.1. Nef;249
14.3.1.1;3.1.1. The protein and its multifunctional activity;249
14.3.1.2;3.1.2. The mechanistic details of the Nef effect on infectivity;251
14.3.1.3;3.1.3. Why is the infectivity of Nef-negative particles defective?;251
14.3.1.4;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
14.3.1.5;3.1.5. Is Nef functioning as a virion protein?;253
14.3.1.6;3.1.6. Does Nef affect incorporation or functionality of other retroviral proteins?;254
14.3.1.7;3.1.7. Does Nef affect virion incorporation of cell-derived components?;254
14.3.2;3.2. Nef is not alone: glycoGag;255
14.3.2.1;3.2.1. How do Nef-like factors promote retrovirus infection?;257
14.3.3;3.3. Are there other Nef-like factors promoting retrovirus infectivity?;258
14.4;4. Final Remarks;258
14.5;References;259
15;Chapter 9: The Cytoplasmic Tail of Retroviral Envelope Glycoproteins;274
15.1;1. Introduction;275
15.2;2. Retroviral Assembly;279
15.3;3. Synthesis and Function of Env;280
15.4;4. Function of the Retroviral Env CT;282
15.4.1;4.1. Anterograde trafficking;282
15.4.2;4.2. Retrograde trafficking;283
15.4.3;4.3. Env packaging into particles;284
15.4.4;4.4. Signaling;286
15.4.5;4.5. Role of the CT of retroviral TM proteins in regulating Env conformation;288
15.4.6;4.6. Role of Gag and virion maturation in regulating Env function;289
15.4.7;4.7. HIV-1 versus SIV gp41 CT;290
15.4.8;4.8. Role of Env in counteracting BST-2;291
15.4.9;4.9. Env CT as a therapeutic target?;292
15.5;5. Conclusions;292
15.6;Acknowledgments;293
15.7;References;293
16;Chapter 10: Molecular Determinants of the Ratio of Inert to Infectious Virus Particles;306
16.1;1. Introduction: A Wide Range of Particle-to-Infectious-Unit Ratio;307
16.2;2. Infectious or Infecting?;308
16.3;3. Defective from the Start;316
16.4;4. Decay in Suspension;328
16.5;5. Abortive Infection;330
16.5.1;5.1. Abortive fates at the cell surface;330
16.5.2;5.2. Intracellular routes to abortive infection;333
16.6;6. Conclusions;336
16.7;Acknowledgment;338
16.8;References;338
17;Chapter 11: The Role of Chance in Primate Lentiviral Infectivity: From Protomer to Host Organism;348
17.1;1. Introduction;348
17.2;2. Host Entry;350
17.2.1;2.1. Modeling acquisition;350
17.2.2;2.2. Modeling initial viral replication and establishment;353
17.3;3. Cell Entry;356
17.3.1;3.1. Infecting a cell;356
17.3.1.1;3.1.1. Cell factors influencing viral entry and cell infection;359
17.3.2;3.2. Preventing the infection of a cell: The role of neutralizing antibodies;360
17.3.2.1;3.2.1. Analogies in antiviral drug treatment;364
17.4;4. Synthesis and Outlook;364
17.5;Acknowledgments;366
17.6;References;367
18;Chapter 12: Virus-Encoded 7 Transmembrane Receptors;374
18.1;1. Evolutionary Context of v7TMRs;375
18.2;2. Functional Divergence from Cellular Chemokine Receptors;383
18.2.1;2.1. Ligand specificity-Broadened repertoire/lack of (known) ligands;383
18.2.2;2.2. Constitutive signaling activity;387
18.2.3;2.3. Constitutive endocytosis;389
18.2.4;2.4. Homo- and heterodimerization of v7TMRs;390
18.3;3. Biological Roles of Viral CKRs;392
18.3.1;3.1. Oncogenesis, angiogenesis, and vascular disease;392
18.3.1.1;3.1.1. Beta 27/28 and 33;395
18.3.1.2;3.1.2. Gamma 74;397
18.3.1.3;3.1.3. Gamma BILF1;398
18.3.2;3.2. Tissue-specific tropism and virus persistence/latency;399
18.3.2.1;3.2.1. Beta 27/28;399
18.3.2.2;3.2.2. Beta 33;400
18.3.2.3;3.2.3. Beta 78;401
18.3.2.4;3.2.4. Gamma 74;402
18.4;4. Concluding Remarks;403
18.5;References;403
19;Chapter 13: EBV, the Human Host, and the 7TM Receptors: Defense or Offense?;416
19.1;1. EBV Infection;417
19.1.1;1.1. Viral infection, entry, and tropism;417
19.1.2;1.2. Lytic replication;419
19.1.3;1.3. Latent infection;420
19.1.4;1.4. Regulation of latency, replication, and virus reactivation;422
19.2;2. Immune Response and Immune Evasion;423
19.3;3. EBV-BILF1-A Virus-Encoded 7TM Receptor with Immune Evasive Functions;425
19.3.1;3.1. Immune evasion strategy of EBV-BILF1;425
19.3.2;3.2. Signaling and tumorigenesis of EBV BILF1;427
19.4;4. EBI2: An Endogenous 7TM Receptor Manipulated by EBV;428
19.4.1;4.1. A family of oxysterols acts as ligands for the EBI2 receptor;428
19.4.2;4.2. Roles of the EBI2-oxysterol axis in the immune response;430
19.4.3;4.3. A potential role for the EBI2-oxysterol axis in EBV infection;431
19.5;5. Manipulation of the Host Immune System 7TM Receptors and Ligands by EBV-The Chemokine System;432
19.6;6. EBV-Associated Diseases;435
19.6.1;6.1. Infectious mononucleosis;435
19.6.2;6.2. Diseases in immunocompetent patients;438
19.6.3;6.3. Diseases in immunocompromised patients;438
19.7;7. Drug-Target Potential;439
19.8;8. Conclusions;440
19.9;Acknowledgment;440
19.10;References;440
20;Index;450
21;Color Plates;459

Leseproben

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...