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National Institute of Allergy and Infectious Diseases, NIH - Volume 1: Frontiers in Research
of: Vassil St. Georgiev, Karl Western, John J. McGowan
Humana Press, 2008
ISBN: 9781597455695 , 530 Pages
Format: PDF, Read online
Copy protection: DRM
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National Institute of Allergy and Infectious Diseases, NIH - Volume 1: Frontiers in Research
Dedication
6
Preface
7
Acknowledgments
9
Table of Contents
11
Contributors
15
Part I: Introduction
20
National Institute of Allergy and Infectious Diseases (NIAID): An Overview
21
Part II: Microbiology and Infectious Diseases
28
Section 1: Emerging and Re-Emerging Infections
29
Chapter 1
31
Biotools for Determining the Genetics of Susceptibility to Infectious Diseases and Expediting Research Translation Into Effective Countermeasures
31
1.1 Introduction
31
1.1.1 A Genetically Diverse, Genomically Well Defined Reference Mouse Panel Afford an Ideal Model for a Systems Biology Approach to Infectious Diseases
31
1.1.2 Studies on the Genetics of Susceptibility to Invasive Group A Streptococcal (GAS) Sepsis Illustrate the Utility of RI Mice in Infectious Disease Research
33
References
34
Chapter 2
37
Spore Surface Components and Protective Immunity to Bacillus anthracis
37
2.1 Introduction
37
2.1.1 Spore Surface Structure
37
2.2 Spores and Host Interaction
38
2.3 Spores and Protective Immunity
39
References
41
Chapter 3
43
New Candidate Anthrax Pathogenic Factors
43
3.1 Introduction
43
3.2 History of Anthrax Toxins Discovery
43
3.3 Genetic Evidence of LT Role
44
3.4 LT Potential in Animals and Cell Culture
45
3.5 Anti-LT Therapy in Anthrax
45
3.6 Spore Resistance in the Host, a New Function of LT
46
3.7 Anthrax Apoptosis, Life-Critical Organs, and Inflammation
47
3.8 Candidate New Pathogenic Factors
48
3.9 Anthrax Hemolysins
49
3.10 Anthrax Proteases Other Than LT
49
3.11 Non-cytotoxic Pathogenic Mechanisms
50
3.12 Conclusion
51
References
51
Chapter 4
55
Ehrlichiae and Ehrlichioses: Pathogenesis and Vector Biology
55
4.1 Introduction
55
4.2 Genomic Studies and Potential Virulence Factors
55
4.3 Ehrlichial Monocyte Entry, Developmental Stages, Differential Outer Membrane Protein Expression, and Manipulation of Host Defenses
57
4.4 Clinical Manifestations and Pathology of HME
59
4.5 Current Status of Animal Models
59
4.6 Characteristics of the Protective and Detrimental Immune Responses to Ehrlichiae
61
4.7 Tick Vectors, Ecology, and Ehrlichial Transmission
61
4.8 Conclusions
61
References
62
Chapter 5
65
Multiple Locus Variable Number Tandem Repeat (VNTR) Analysis (MLVA) of Brucella spp. Identifies Species-Specific Markers and Insights into Phylogenetic Relationships
65
5.1 Introduction
65
5.2 Materials and Methods
66
5.2.1 DNA Preparation
66
5.2.2 Identification of VNTR Sequences
66
5.2.3 PCR Screening for Variability
66
5.2.4 MLVA Design and Multiplex PCR Conditions
66
5.2.5 Automated Genotype Analysis
67
5.2.6 Brucella Isolates
67
5.2.7 Phylogenetic Analysis
67
5.3 Results
68
5.3.1 Identification of VNTR Sequences
68
5.3.2 PCR Screening for Variability
68
5.3.3 MLVA
68
5.3.4 VNTR Marker Diversity
68
5.3.5 Brucella Genotypes and Species-Specific Alleles
68
5.3.6 Brucella Genetic Relationships
68
5.4 Discussion
69
References
71
Chapter 6
73
Expression of the MtrC-MtrD-MtrE Efflux Pump in Neisseria gonorrhoeae and Bacterial Survival in the Presence of Antimicrobials
73
6.1 Overview of Neisseria gonorrhoeae , Epidemiology, Antibiotic Resistance, and Resistance to Host Defenses
73
6.2 Efflux Pumps Possessed by N. gonorrhoeae
74
6.2.1 Discovery of Bacterial Efflux Pumps
74
6.2.2 Neisserial Efflux Pumps
74
6.2.3 The MtrC-MtrD-MtrE Efflux Pump System
75
6.3 Regulation of Efflux Pumps and Other Genes Possessed by N. gonorrhoeae
75
6.3.1 Cis -Acting Control Elements Important in Regulating Control of the mtr Locus
75
6.3.1.1 Regulatory Properties of a 13-bp Inverted Sequence
76
6.3.1.2 CE Positioned Upstream of mtrCDE
76
6.3.2 Trans-acting Regulatory Proteins That Control mtrCDE Expression
76
6.3.2.1 DNA-binding and Transcriptional Regulatory Properties of MtrR
76
6.3.2.2 Transcriptional Regulatory Properties of MtrA
77
6.4 Biologic Functions and Significance of the Gonococcal MtrC-MtrD-MtrE Efflux Pump
77
6.4.1 Export of Antibiotics by MtrC-MtrD-MtrE and Clinical Relevance
78
6.4.2 Export of an Over-The-Counter Biocide/ Spermicide N-9
78
6.4.3 Export of Host-Derived Antimicrobials
78
6.4.4 Evidence that the MtrC-MtrD-MtrE Efflux System is Important in Gonococcal Pathogenicity
78
6.5 Conclusions and Future Studies
79
References
80
Section 2: Tuberculosis
83
Chapter 7
85
What can Mycobacteriophages Tell Us About Mycobacterium tuberculosis ?
85
7.1 Introduction: The Challenges of Studying Mycobacterium tuberculosis
85
7.2 The Big Wide World of Bacteriophages
85
7.3 Insights into Mycobacteriophage Genomes
85
7.4 Mycobacteriophage Morphologies
86
7.5 Mycobacteriophage Genetic Mosaicism
86
7.6 How is Genetic Mosaicism Generated?
88
7.7 All in the Phamily
88
7.8 Acquisition of Host Genes by Mycobacteriophages
88
7.9 Development of Mycobacteriophage-based Genetic Tools
89
7.10 Integration-proficient Plasmid Vectors
89
7.11 Development of tRNA Suppressors
90
7.12 Immunity-based Selectable Markers
90
7.13 Recombineering
91
7.14 Physiological Consequences of Phage Integration
91
7.15 Conclusion
92
References
92
Chapter 8
95
Clinical Mycobacterium tuberculosis Strains Differ in their Intracellular Growth in Human Macrophages
95
8.1 Introduction
95
8.2 TB Infection and Disease
95
8.3 Strain-specific MTB Pathogenesis
95
8.3.1 Murine Models of Virulence
95
8.3.2 Macrophage Models of Virulence
96
8.4 Virulence Assessment of Household Transmitted Isolates
97
8.5 Virulence Assessment of Strains of the Beijing Family
97
8.6 Summary
98
References
98
Chapter 9
101
Mechanisms of Latent Tuberculosis: Dormancy and Resuscitation of Mycobacterium tuberculosis
101
9.1 Introduction
101
9.2 In Vitro Models of Mycobacterial Dormancy
101
9.2.1 Semi-anaerobic Model of Non-culturability in M. tuberculosis
101
9.2.2 Growth Under Unbalanced Conditions
102
9.2.3 Mycobacterial NC Forms: Features and Characteristics
102
9.3 Resuscitation-promoting Factor (Rpf)
103
9.3.1 Mechanisms of Rpf Action
103
9.4 Conclusion
105
References
106
Chapter 10
109
Separating Latent and Acute Disease in the Diagnosis of Tuberculosis
109
10.1 Introduction
109
10.2 Antigenics and Genomics: The Key to Improved TB Diagnosis
109
10.3 What Can We Learn From the Magnitude of the Immune Response?
110
10.4 What Can We Learn From the Nature of the Immune Response?
111
10.5 What Can We Learn From the Specificity of the Immune Response?
112
10.6 Conclusions
114
References
115
Chapter 11
119
Mutant Selection Window Hypothesis: A Framework for Anti-mutant Dosing of Antimicrobial Agents
119
11.1 Introduction
119
11.2 Mutant Prevention Concentration
119
11.3 Mutant Selection Window Hypothesis
120
11.4 Stepwise Accumulation of Resistance Mutations
121
11.5 Extension of the Selection Window to Dynamic Systems
121
11.6 Clinical Test of the Window Hypothesis
121
11.7 Correction for Lethal Agents
122
11.8 Concluding Remarks
122
References
122
Section 3: Avian Influenza
125
Chapter 12
127
The NIAID Influenza Genome Sequencing Project
127
12.1 Background
127
12.2 Purpose and Process
127
12.2.1 How to Collaborate With the NIAID Influenza Genome Sequencing Project
128
12.3 Progress To Date
128
12.3.1 Seasonal Human Influenza Virus Collections
128
12.3.2 Avian and Other Animal Virus Collections
129
12.3.3 Scientific Insights
129
12.4 The Future
130
References
131
Chapter 13
133
Lessons From the 1918 Spanish Flu Epidemic in Iceland
133
13.1 Introduction
133
13.2 Materials and Methods
133
13.2.1 Historical and Medical Data
133
13.2.2 Birth Data
133
13.2.3 Statistics
133
13.3 Description of the Epidemic by the Lay Press
133
13.3.1 Arrival of the Flu: Early News
133
13.3.2 Responses by the Health Authorities
134
13.3.3 The Shock and its Aftermath
134
13.4 Description of the Epidemic According to Health Report of the CMO
134
13.4.1 Index Cases and Early Spread of the Epidemic
134
13.4.2 Incubation Period, Attack Rate, and Case Fatality
134
13.4.3 Responses and Quarantine Measures
136
13.5 Dr. Thoroddsen’s Description of the Epidemic
136
13.5.1 Rise and Fall Within 40 Days
136
13.5.2 Characteristics of the Illness
137
13.5.3 The Spanish Flu in Perspective
139
13.6 Summary and Lessons Learned
139
References
140
Chapter 14
141
Control of Notifiable Avian Influenza Infections in Poultry
141
14.1 Introduction
141
14.2 Prevention of AI
142
14.3 Vaccination for AI
142
14.4 Emergency Vaccination
143
14.5 Vaccination Versus Pre-emptive Culling
144
14.6 Prophylactic Vaccination
145
14.7 Conclusions
145
References
146
Chapter 15
149
Understanding the Complex Pathobiology of High Pathogenicity Avian Influenza Viruses in Birds
149
15.1 Introduction
149
15.2 Pathobiology Concepts
149
15.2.1 Ecology and Epidemiology
149
15.3 Critical Virus Factors in Infection and Virulence
150
15.4 Pathogenesis of HPAI Virus Infections in Chickens
150
15.5 Pathobiology of HPAI
152
15.5.1 Gallinaceous Poultry
152
15.5.2 Pathobiology Groups
152
15.5.3 Domestic Ducks and H5N1 HPAI Viruses
154
15.5.4 Other Species of Birds
155
15.6 Summary
157
References
157
Section 4: Prophylactics and Therapeutics for Infectious Diseases
161
Chapter 16
163
Development of Prophylactics and Therapeutics Against the Smallpox and Monkeypox Biothreat Agents
163
16.1 Introduction
163
16.2 Human Poxvirus Diseases
163
16.2.1 Smallpox
163
16.2.1.1 History
163
16.2.1.2 Clinical Disease
164
16.2.1.3 Person-to-Person Transmission
164
16.2.1.4 VARV as a Potential Biothreat Agent
165
16.2.2 Human Monkeypox
165
16.2.2.1 History
165
16.2.2.2 Clinical Disease
166
16.2.2.3 Person-to-Person Transmission of MPXV
166
16.2.2.4 Human Monkeypox: An Emerging Infectious Disease
166
16.2.2.4.1 Increasing Geographic Range
166
16.2.2.4.2 Increasing Incidence of Disease
166
16.3 Recognition of the Threat of Bioweapons and Emerging Infectious Diseases
167
16.4 Historic Prophylactic and Therapeutic Treatments for Human Poxvirus Diseases
168
16.4.1 Smallpox Vaccines
168
16.4.1.1 Traditional Vaccines: Live, Animal Passaged and Virulent
168
16.4.1.2 Type and Frequency of Complications
168
16.4.1.3 Contraindications to Vaccination
168
16.4.2 Vaccinia Immune Globulin (VIG)
168
16.4.3 Antivirals
168
16.5 New Risks Require New Treatment Modalities
169
16.6 A New Paradigm for Licensure of Human Poxvirus Vaccines and Drugs
169
16.6.1 Animal Efficacy Rule
169
16.6.2 Historic Animal Models for Preclinical Evaluation of Human Orthopoxvirus Vaccines and Drugs
170
16.6.2.1 Vaccinia Virus in Mice
170
16.6.2.2 CPXV in Mice
170
16.6.3 New Models for Preclinical Evaluation of Human Orthopoxvirus Vaccines and Drugs
171
16.6.3.1 Mousepox: ECTV in Mice
172
16.6.3.2 Rabbitpox: VACV in Rabbits
172
16.6.3.3 Monkeypox: MPXV in Non-human Primates
173
16.6.4 New Drug Applications and New Biological Licenses for Therapeutic and Prophylactic Treatments of Human Orthopoxvirus Infections
173
16.6.4.1 New Vaccines
173
16.6.4.1.1 Acambis 2000 Vaccine
174
16.6.4.1.2 MVA Vaccine
174
16.6.4.2 New Antivirals
174
16.6.4.2.1 CMX001
174
16.6.4.2.2 ST-246
175
16.6.5 Financing Development of Products for Human Orthopoxvirus Infections That Have No Commercial Market
175
References
175
Chapter 17
181
The Hierarchic Informational Technology for QSAR Investigations: Molecular Design of Antiviral Compounds
181
17.1 Introduction
181
17.2 Materials and Methods
182
17.2.1 Simplex Representation of Molecular Structure (SiRMS)
182
17.2.1.1 1D Models
182
17.2.1.2 2D Models
183
17.2.1.3 3D Models
184
17.2.1.4 4D Models
184
17.2.2 The Whole-Molecule Parameters
184
17.2.3 Statistical Processing
185
17.2.3.1 Validation of QSAR
185
17.2.3.2 Automatic Variable Selection (AVS) Strategy in PLS
185
17.2.3.3 Removal of Highly Correlated Descriptors
185
17.2.3.4 Trend-Vector Procedure
185
17.2.3.5 Genetic Algorithm
186
17.2.4 Estimation of Factors Determining the Interaction With the Biological Target
186
17.2.5 Inverse Task Solution: Molecular Design of Novel Compounds with Given Level of Activity
186
17.2.6 Virtual Screening of Activity: Estimation of Domain Applicability of PLS Models
186
17.2.7 Comparison of HIT with Other QSAR Methods
187
17.2.8 Investigation of Anti-influenza Activity 3,4
187
17.3 Results and Discussion
189
17.4 Conclusion
191
References
195
Chapter 18
197
Antivirals for Influenza: Novel Agents and Approaches
197
18.1 Introduction
197
18.2 NA Inhibitors
199
18.2.1 Intravenous Zanamivir
199
18.2.2 Peramivir
199
18.2.3 A-315675
200
18.2.4 Long-acting NA Inhibitors
200
18.2.4.1 Multivalent LANIs
200
18.2.4.2 CS-8958
201
18.3 Nucleoside Analogs
201
18.3.1 T-705
201
18.3.2 Viramidine and Ribavirin
201
18.4 HA and Attachment Inhibitors
202
18.4.1 DAS 181
202
18.4.2 Cyanovirin-N
202
18.4.3 Entry Blocker (EB)
203
18.5 Protease Inhibitors
203
18.6 Serotherapy
203
18.7 RNA Interference
204
18.8 Interferons
204
18.9 Host Cellular Targets
204
18.10 Combination Chemotherapy
205
References
205
Chapter 19
211
Anti-Infectious Actions of Proteolysis Inhibitor epsilon-Aminocaproic Acid (epsilon-ACA)
211
19.1 Introduction
211
19.2 Materials and Methods
211
19.3 Results and Discussion
212
References
216
Chapter 20
217
A New Highly Potent Antienteroviral Compound
217
20.1 Introduction
217
20.2 Oxoglaucine
217
Section 5: Russian Perspectives in Emerging and Re-Emerging Infections Research
221
Chapter 21
223
Reduction and Possible Mechanisms of Evolution of the Bacterial Genomes
223
21.1 Introduction
223
21.2 Examples of Genome Reduction
223
21.3 Traditional View on the Mechanism of Genomes’ Reduction
225
21.4 Facts that Cannot be Explained by the Universally Recognized Concept of Genome Reduction
225
21.5 Molecular Mechanisms of Genomic Rearrangements
226
21.5.1 Types of Recombination Sites: RNA, Integrons
226
21.5.2 The Role of Movable Elements and Repeats
226
21.5.3 Scenario of Rearrangements
227
21.6 Polynucleotide (Pn)-selection
227
21.7 Pulsing Genome Hypothesis
229
21.7 Do Any Indications of Genome Pulsing Exist?
229
21.8 Conclusion
229
References
230
Chapter 22
233
Interaction of Yersinia pestis Virulence Factors with IL-1R/TLR Recognition System
233
22.1 Introduction
233
22.2 V Antigen Y. pestis (LcrV)
233
22.2.1 LcrV Is a Short- and Long-term Weapon of Y. pestis
233
22.2.2 LcrV of Y. pestis Has Two Binding Sites for Interaction With TLR2 and Receptor-bound Human IFN-gamma
233
22.2.3 Apoptosis Induction in Human Thymocytes by LcrV 68–326 and Human IFN-gamma
235
22.3 Capsular Antigen F1 (Caf1)
235
22.3.1 Biogenesis of Y. pestis Capsule
235
22.3.1.1 Caf1 Biosynthesis and Dimer Formation in the Bacterial Periplasm: Caf1 Dimer is a Minimal Building Block of Capsule
235
22.3.1.2 Hydrodynamic Properties of Caf1
237
22.3.1.3 Caf1 Dimer is a Minimal Cooperative Block of Y. pestis Capsule
238
22.3.1.4 Role of Tyrosine Residues in the Caf1 Dimer Formation
238
22.3.1.5 Spatial Organization of the Capsule
239
22.3.1.6 Theory of Y. pestis Capsule Melting in Aerosol Microdroplets
239
22.3.2 Interaction of Caf1 Dimer With IL-1R on Target Cells and Soluble IL-1beta
240
22.4 Plasminogen Activator (Pla)
240
22.4.1 Interaction of Pla With Human Cells
240
22.4.2 Synergistic Protection of Mice Against Y. pestis by LcrV and Pla
240
22.5 Conclusion
241
References
241
Chapter 23
245
IS481-Induced Variability of Bordetella pertussis
245
23.1 Introduction
245
23.2 The Transposition of IS481 in E. coli Cells
245
23.3 The Transposition of IS481 in B. pertussis Cells
246
23.4 IS481 Transposition in B. pertussis Cells is bvg -Depends Process
247
23.5 IS Transposition is Mechanism for Phase Variation in Bordetella
248
References
248
Chapter 24
251
Microarray Immunophosphorescence Technology for the Detection of Infectious Pathogens
251
24.1 Introduction
251
References
257
Chapter 25
259
Development of Immunodiagnostic Kits and Vaccines for Bacterial Infections
259
25.1 Introduction
259
25.1 Immunoreagents for Immunodiagnostic Kits
259
25.1.1 Polyclonal, Monoclonal,
259
25.1.1.1 Polyclonal Abs (PAbs)
259
25.1.1.2 Monoclonal Abs (MAbs)
260
25.1.1.3 Anti-idiotypic (Anti-Id) Abs
261
25.1.2 Abs With Desired Specificity Obtained Using Other Immunological Approaches (Directed Immunogenesis)
261
25.1.2.1 The Use of Inbred Biomodels With Certain Genotypes Providing Induction of Abs to Some Desired Antigens/Epitopes of a Complex Immunizing Agent and Tolerance to the Others
261
25.1.2.2 Inoculation of Cross-Reactive Immunizing Agents to Newborn Mice Following Injection of the Antigen to 6- to 8-Week-Old Mice
261
25.1.3 Murine Immune Ascitic Fluids as a Source for Obtaining Different Kinds of Abs
262
25.2 Prospects for New Vaccine Development
262
25.2.1 Vaccines Against Pathogens With Extracellular and Intracellular Life Cycles
263
25.2.2 Vaccines With Decreased Reactogenicity and Increased Immunogeneity
264
25.2.2.1 Organisms With Mutation in the Genes of Lipid A: Toxic Part of Bacterial LPS
264
25.2.2.2 Anti-idiotypic Vaccines
264
25.3 Methods for the Control of Biosynthesis of Protective Antigens for Vaccines During Their Manufacture
265
References
265
Section 6: Perspectives in Emerging and Re-Emerging Infections-Research in Central Asia and Caucasus
267
Chapter 26
269
Research in Emerging and Re-emerging Diseases in Central Asia and the Caucasus: Contributions by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health
269
26.1 Introduction
269
26.2 Research Grants
269
References
270
Chapter 27
271
Disease Surveillance in Georgia: Benefits of International Cooperation
271
27.1 Introduction
271
27.2 Surveillance System in Georgia
271
27.3 The National Center for Disease Control and Medical Statistics (NCDC) of Georgia
271
References
273
Chapter 28
275
Epidemiology (Including Molecular Epidemiology) of HIV, Hepatitis B and C in Georgia: Experience From U.S.-Georgian Collaboration
275
28.1 Introduction
275
28.2 Completed Projects
275
28.3 Major Epidemiology Findings
275
28.4 Molecular Epidemiology of HIV
276
28.5 Epidemiology of HCV
278
28.6 Other Accomplishments of the US-Georgian Collaboration
279
Chapter 29
281
The National Tuberculosis Program in the Country of Georgia: An Overview
281
29.1 Background
281
29.2 Methods
281
29.2.1 The Infrastructure of the NTP
281
29.2.2 Political Commitment and Financing
281
29.2.3 Diagnosis of TB
281
29.2.3.1 Laboratory Diagnostic Facilities
282
29.2.4 Tuberculosis Treatment
282
29.2.4.1 Directly Observed Treatment (DOT)
282
29.2.5 Monitoring and Evaluation System
282
29.2.5.1 Permanent Reporting System
282
29.2.5.2 Supervision
282
29.3 Results and Future Plans
283
29.3.1 Administrative/Budgeting Measures
283
29.3.1.1 Political Commitment and Financing
283
29.3.1.2 Partner and Donor Organizations
283
29.3.2 TB Case Finding
283
29.3.2.1 Laboratory Network Optimization
283
29.3.2.1.1 Culture Examination and DST
284
29.3.3 TB Treatment
284
29.3.3.1 DOT
284
29.3.3.2 DR-TB Treatment
284
29.3.3.3 Regular Drug Supplies
284
29.3.4 Permanent Reporting System
284
29.3.5 TB Control in the Penitentiary System
285
29.3.6 Scientific Research on TB in Georgia in the Context of Global Goals
285
29.4 Conclusion
285
References
285
Part III: Human Immunodeficiency Virus and AIDS
287
Chapter 30
289
Virus Receptor Wars: Entry Molecules Used for and Against Viruses Associated with AIDS
289
30.1 Introduction
289
30.2 HIV Entry and Neutralization of Infection
290
30.2.1 The Entry Mechanism of HIV
290
30.2.2 The HIV Neutralizing Antibody Problem
291
30.2.3 A Novel Bifunctional HIV-neutralizing Protein Based on Sequential Receptor Interactions
291
30.3 KSHV Entry and Receptor Identification
292
30.3.1 Entry Mechanisms of Herpesviruses
292
30.3.2 Identification of KSHV Receptor by Functional cDNA Library Screening
292
30.3.3 Potential Significance of xCT for KSHV Pathogenesis
294
30.4 Conclusions
294
References
294
Chapter 31
297
HIV Latency and Reactivation: The Early Years
297
31.1 HIV as a Retrovirus: A New Pathogenic Entity
297
31.2 Surrogate Model Systems for Studying HIV Infection In Vitro
298
31.3 Cytokines as Physiological Factors Controlling HIV Latency and Replication
300
31.4 Cytokine-mediated Modulation of HIV Replication: From Cell Lines to Primary Cells Infected In Vitro or In Vivo
301
31.5 Conclusions and Perspectives
303
References
303
Chapter 32
307
HIV-1 Sequence Diversity as a Window Into HIV-1 Biology
307
32.1 Overview
307
32.2 Complexity of Newly Transmitted Virus
307
32.3 Compartmentalization and HIV-associated Dementia
308
32.4 Source of Compartmentalized Virus in the CNS
309
32.5 Evolution of CCR5 Usage to CXCR4 Usage
309
32.6 CCR5 and CXCR4 Usage Differences Between Subtype B and Subtype C HIV-1
310
32.7 Neutralizing Antibodies Against HIV-1 Env
311
32.8 Conclusion
311
References
312
Chapter 33
317
Human Monoclonal Antibodies Against HIV and Emerging Viruses
317
33.1 Introduction
317
33.2 HIV
318
33.2.1 Anti-HIV Antibodies Elicited by Infection or Immunization
318
33.2.2 HIV-1-neutralizing hmAbs Against the Env
318
33.2.3 Evidence That Antibodies Can Affect HIV-1 Replication in Humans
319
33.2.4 Developing Antibodies With Improved Neutralizing Activity
319
33.2.5 Conclusions (HIV)
319
33.3 SARS-CoV
320
33.3.1 NiV and HeV
321
33.3.2 Conclusions (SARS-CoV and Henipaviruses)
322
References
323
Chapter 34
327
Biological Basis and Clinical Significance of HIV Resistance to Antiviral Drugs
327
34.1 Introduction
327
34.2 Generation of HIV-1 Drug Resistance
327
34.3 Inhibitors of RT
329
34.4 PR Inhibitors
330
34.5 ARV Drug Resistance in Non-B Subtypes of HIV-1 Group M
331
34.6 Transmission of HIV Drug-Resistance
331
34.7 Conclusion
333
References
333
Chapter 35
337
NIAID HIV/AIDS Prevention Research
337
35.1 HIV/AIDS Pandemic
337
35.2 HIV/AIDS Prevention Research
338
35.3 National Institute of Allergy and Infectious Diseases (NIAID) HIV Prevention Research
340
35.4 Conclusion
342
References
342
Chapter 36
345
Epidemiological Surveillance of HIV and AIDS in Lithuania
345
36.1 Introduction
345
36.2 HIV Epidemiological Situation
345
36.3 General Overview
345
36.4 AIDS Cases
348
36.5 HIV/TB Co-infection in Lithuania
350
36.6 HIV Outbreak in Alytus CF
350
36.6.1 State Mental Health Center, Lithuanian AIDS Center, and Prison Department Data, 2005
350
36.6.2 Prison Department Data, 2005
350
36.7 HIV Transmission Through Sexual Contacts
351
36.8 Homosexual Transmission
352
36.9 Heterosexual Transmission
353
36.10 SWs
353
36.11 IDU
353
36.12 Mother-to-Child Transmission
354
36.13 Conclusions
354
References
355
Part IV: Immunology and Vaccines
357
Section 1: Immunomodulation
359
Chapter 37
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TACI, Isotype Switching, CVID, and IgAD
361
37.1 APRIL, BAFF, and Their Receptors
361
37.2 Isotype Switching
362
37.3 CVID and IgAD
362
37.4 Mutations in TACI Result in CVID and IgAD
363
37.5 Mechanisms of B-cell Deficiency in Patients with TACI Mutations
364
37.6 Penetrance of TACI Mutations
364
37.7 Conclusion and TherapeuticImplications
365
References
365
Chapter 38
367
A Tapestry of Immunotherapeutic Fusion Proteins: From Signal Conversion to Auto-stimulation
367
38.1 Introduction
367
38.2 Costimulator and Coinhibitor Paints
368
38.3 Trans Signal Converter Proteins (TSCP)
369
38.4 Cis Loop-Back Proteins (CLAP)
370
38.5 Mining the Fusion Protein Concept
371
References
371
Chapter 39
375
A Role for Complement System in Mobilization and Homing of Hematopoietic Stem/Progenitor Cells
375
39.1 Introduction
375
39.2 The Role of C in Stem Cell Trafficking
375
39.2.1 Retention, Mobilization, and Engraftment of HSPCs
375
39.2.1.1 Retention of HSPC in BM
375
39.2.1.2 Mobilization of HSPC to PB
376
39.2.1.3 Homing of HSPC After Transplantation
377
39.2.2 Role of C in Inflammation and Tissue Injury
377
39.2.3 C3 is Secreted by BM Stroma Cells and Activated/Cleaved During Marrow Injury
377
39.2.4 C3aR Increases Incorporation of CXCR4 Into Membrane Lipid Rafts and This Increases Responsiveness of the CXCR4 Receptor to an SDF-1 Gradient
378
39.2.5 CR3 Tethers Hematopoietic Progenitor Cells (HPC) to iC3b Deposits on Irradiated Stroma
379
39.2.6 The Need for New Strategies to Improve Mobilization, Homing, and Expansion of HSPC
379
39.3 Conclusion
380
References
380
Chapter 40
383
Post-translational Processing of Human Interferon- gamma Produced in Escherichia coli and Approaches for its Prevention
383
40.1 Introduction
383
40.2 Experimental Procedures
384
40.2.1 Purification of rhIFN-gamma
384
40.2.2 Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE)
384
40.2.3 Liquid Chromatography/Electrospray Ionization-Mass Spectrometry (LC/ESI-MS)
384
40.2.4 Gel Filtration Chromatography
384
40.2.5 Kynurenine Bioassay
384
40.2.6 Fluorescence Measurements
385
40.3 Results and Discussion
385
40.3.1 Post-translational Processing of rhIFN-gamma
385
40.3.2 Are rhIFN-gamma Covalent Dimers Biologically Active?
385
40.3.3 Inhibition of Glycation and Stabilization of rhIFN-gamma
387
40.4 Conclusions
389
References
389
Section 2: Autoimmunity
393
Chapter 41
395
B-cell Dysfunctions in Autoimmune Diseases
395
41.1 B Lymphocytes Play Multiple Roles in the Autoimmune Pathologic Process
395
41.2 Multiple Mechanisms Contribute to B-cell Tolerance to Self
396
41.3 Regulation of B-cell Survival
397
41.4 B-cell Longevity and Autoimmunity
398
41.5 B-cell Survival in Human Systemic Autoimmune Disease
398
41.6 Autoimmunity and BcR-mediated Signaling
398
41.7 Therapeutic Implications
399
References
400
Chapter 42
403
A Model System for Studying Mechanisms of B-cell Transformation in Systemic Autoimmunity
403
42.1 Introduction: Evidence for a Strong Association Between Systemic Autoimmunity and B-cell Lymphoma
403
42.2 Evidence to Support a Role for Sustained Ag Drive in Lymphoma Etiology
404
42.3 IL-10 and BAFF as Potential Links Between B-cell Hyperactivity, Systemic Autoimmunity and B-cell Transformation
404
42.4 FasL-deficient Mice as a Model System for Studying Relationships Between Systemic Autoimmunity and B-cell Lymphomagenesis
405
42.5 Activated CD21/CD23lo B Cells are the Likely Precursors of PL
406
42.6 IL-10 Is Not Essential for the Development of Autoimmunity or B-cell Lymphomas in gld Mice
409
42.7 Conclusions
411
References
411
Chapter 43
415
Breach and Restoration of B-cell Tolerance in Human Systemic Lupus Erythematosus (SLE)
415
43.1 Introduction
415
43.1.1 B Cells as Central Pathogenic Players in SLE
415
43.1.2 B-cell Tolerance as a Critical Factor in Autoimmunity
415
43.1.3 Experimental Approaches to the Study of Human B-cell Tolerance
416
43.1.4 B-cell Depletion in the Treatment of SLE
417
43.1.5 Restoration of B-cell Tolerance After Prolonged B-cell Depletion
420
43.2 Discussion
420
References
422
Section 3: Infection and Immunity
425
Chapter 44
427
Dendritic Cells: Biological and Pathological Aspects
427
44.1 Introduction
427
44.2 DC Biology
427
44.2.1 Activation of DCs and Launching of Protective Immunity
427
44.2.1.1 Activation of DCs by Microbial Components
428
44.2.1.2 Activation of DCs by Products of Dying Cells
429
44.2.1.3 DCs as Choreographers of the Immune System
429
44.2.1.4 Activation of DCs by Innate Immune Cells and Tissue Environment
430
44.2.1.5 DC Interaction With Adaptive Immune Cells
431
44.2.2 Maintenance of Tolerance by DCs
431
44.3 DC Subsets
431
44.3.1 Myeloid DC subsets
432
44.3.2 Blood DC Subsets
433
44.3.3 DC Subsets Regulate B-cell Responses
434
44.4 DCs in Diseases
434
44.4.1 DCs in Autoimmunity
434
44.4.2 DCs and Allergy
434
44.4.3 DCs and Infection
435
44.4 DCs and Cancer
435
44.5 Design of Vaccines Through DC Biology
435
44.5.1 Ex Vivo DC-based Vaccines
436
44.5.2 Targeting DCs In Vivo
436
44.6 Conclusion
436
References
436
Chapter 45
447
Immunomic and Bioinformatics Analysis of Host Immunity in the Vaccinia Virus and Influenza A Systems
447
45.1 Introduction
447
45.2 Demonstrating the Success of Bioinformatics-based Epitope Predictions Using VACV as a Model Pathogen
447
45.2.1 Validation of Bioinformatics-based Epitopeprediction in the H-2b Murine Model System
448
45.2.2 Identification of HLA-restricted Class I VACV-specific Epitopes
448
45.2.2.1 VACV-specific CD8+ T-cell Epitope Identification in HLA-transgenic Mice
448
45.2.2.2 VACV-specific CD8 + T-cell Epitope Identification in Human Vaccines
449
45.2.3 Structural Features of the Antigens Recognized by Cellular Immunity
449
45.3 Immune Epitope Database and Analysis Resource (IEDB) and Mapping the Known Immune Responses Against Influenza A Virus
449
45.3.1 The IEDB
449
45.3.2 Populating and Querying the Database and its Associated Analysis Resource
450
45.3.3 An Analysis of the Influenza A Data Available in the Scientific Literature
450
45.4 Conclusion
451
References
452
Chapter 46
453
Immunoreactions to Hantaviruses
453
46.1 What Are Hantaviruses?
453
46.2 Cell Receptors
453
46.3 The Struggle Between Cells and Hantaviruses
454
46.3.1 Monocytes/macrophages
454
46.3.2 Dendritic Cells (DCs)
454
46.3.3 Endothelial Cells
455
46.4 Apoptosis
458
46.5 Conclusion
459
References
460
Chapter 47
463
Innate Immunity to Mouse Cytomegalovirus
463
47.1 Introduction
463
47.2 Macrophages and DCs as Components of the Innate Immunity to MCMV
463
47.3 NK cells and Their Receptors
465
47.4 NK Cells in MCMV Infection: Resistant and Sensitive Mouse Strains
468
47.5 CMV Strategies to Evade NK Responses
468
47.5.1 MCMV Downregulation of NKG2D Ligands
470
47.6 Conclusion
470
References
471
Section 4: Vaccines
475
Chapter 48
477
Research and Development of Chimeric Flavivirus Vaccines
477
48.1 An Introduction to Flaviviruses
477
48.1.1 Flavivirus Overview
477
48.1.1.1 YF
477
48.1.1.2 Japanese Encephalitis (JE)
477
48.1.1.3 Dengue Virus (DV)
477
48.1.1.4 West Nile
478
48.1.2 Wanted: New and Better Vaccines
479
48.1.2.1 YF Vaccine as Exemplar
479
48.1.2.2 JE Vaccines
479
48.1.2.3 Dengue Vaccines in Development
479
48.1.2.4 WN vaccines in development
480
48.1.2.5 CV Vaccines
480
48.2 Construction of Chimeric Flaviviruses
480
48.3 Preclinical Testing of Chimeric Flaviviruses
481
48.3.1 Safety Testing in Animal Models
481
48.3.1.1 Neurovirulence
481
48.3.1.2 Neuroinvasiveness
482
48.3.1.3 Extraneural pathology
482
48.3.1.4 Viremia
482
48.3.2 Efficacy Testing in Animal Models
483
48.3.2.1 Immunogenicity
483
48.3.2.2 Protection
483
48.3.3 Genetic Stability and Vector Tropism
484
48.3.3.1 Genetic Stability
484
48.3.3.2 Recombination Studies
484
48.3.3.3 Vector Transmission
485
48.4 Clinical Development
485
48.4.1 CV-JE
485
48.4.2 CV-DV
486
48.4.3 CV-WN02
487
48.5 Conclusions
487
References
487
Chapter 49
491
Correlates of Immunity Elicited by Live Yersinia pestis Vaccine
491
49.1 Introduction
491
49.2 Results and Discussion
491
49.2.1 Experimental Outline for Immunization in the Murine Model
491
49.2.2 Murine Humoral Responses
492
49.2.3 Murine T-cell-mediated Responses
493
49.2.4 Human Humoral Responses
494
49.2.5 Human T-cell-mediated Responses
495
49.3 Conclusions
497
References
497
Part V: Building A Sustainable Personal Research Portfolio
499
Chapter 50
501
Strategies for a Competitive Research Career
501
50.1 Introduction
501
50.2 Secure Complementary Funding
501
50.3 Identify and Seek Collaborative Opportunities
501
50.4 Identify and Seize Training Opportunities
502
50.5 Gain Access to Research Administration Infrastructure
503
50.6 Overview of the Essential Components for Building a Sustainable Research Portfolio and Biomedical Research Career
503
Chapter 51
505
Selecting the Appropriate Funding Mechanism
505
51.1 Introduction
505
51.2 Investigator-Initiated Research (Unsolicited Applications)
506
51.2.1 Research Grants (R Series)
506
51.2.2 NIH Research Training and Research Career Development Opportunities (F, K, and T series)
507
51.3 Program Project/Center Grants (P series; Solicited or Unsolicited Applications)
511
51.4 Responding to an Institute-Specific FOAs (Solicited Applications)
511
51.5 Support for International Research
512
Chapter 52
515
Preparing and Submitting a Competitive Grant Application
515
52.1 Introduction
515
52.2 Why Applications Succeed or Fail in the Peer-Review Process
515
52.3 Developing a Competitive and Successful Application
516
52.3.1 Strategies for Success
516
52.3.2 Checklists for the Application Process
516
52.3.3 Advice for New Investigators
517
52.4 The Review Criteria
517
52.4.1 Significance
517
52.4.2 Approach
517
52.4.3 Innovation
517
52.4.4 Investigator
517
52.4.5 Environment
518
52.5 Submission of the Application
518
52.6 Overview of the NIH Peer-Review System
518
52.6.1 COI and Confidentiality
519
50.6.2 NIAID Scientific Review Staff Roles
519
52.7 What Happens During a Review Meeting
519
52.7.1 Streamlining
520
52.7.2 Assigning Priority Scores
520
52.7.3 Budget Recommendations
520
52.7.4 Post-Review
520
52.8 Conclusion
520
52.9 Additional Resources
520
52.9.1 Registration and Application Submission Process Details
520
52.9.1.1 Registration
520
52.9.1.2 Pre-Application
521
52.9.1.3 The Application Process
521
52.9.2 DHHS, NIH Regulations, Policies and Offices that Affect the Submission, Evaluation, and Management of Awards
522
Chapter 53
525
Identifying Research Resources and Funding Opportunities
525
53.1 Introduction
525
53.2 Glossary of Terms
525
53.3 Literature Searching and Other Database Resources
525
53.3.1 Medical Genetics Resources:
526
53.4 Additional NIH/NIAID Research Resources and Networks
527
53.5 National/International Funding Resources
531
Index
537
Color Plates
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