Advances in Virus Research (eBook)

Front Cover 1
Advances in Virus Research 4
Copyright Page 5
Contents 6
Chapter 1: Looking Back in 2009 at the Dawning of Antiviral Therapy Now 50 Years Ago: An Historical Perspective 8
I. Introduction 10
II. Thiosemicarbazones: The First Antiviral Drugs Found Active Against the Poxvirus Vaccinia Virus 11
III. Renaissance of the Poxvirus Inhibitors: Antiviral Drugs Against a Bioterrorist Poxvirus (Variola Virus) Attack 13
IV. Benzimidazole Derivatives: Second Attempt to Launch the Antiviral Chemotherapy Era 15
V. Renaissance of the Benzimidazole Derivatives: Now Turning into Lead Candidates for the Treatment of Human CMV Infections 18
VI. 5-Substituted 2'-Deoxyuridines: Idoxuridine (IDU) and Trifluridine (TFT), the Third and Definitive Attempt to Unleash Antiviral Chemotherapy 20
VII. 5-Substituted 2'-Deoxyuridines: IDU (and TFT) as the Starting Point(s) for Other 5-Substituted 2'-Deoxyuridines, that is, BVDU [(E)-5-(2-Bromovinyl)-2'-Deoxyuridine] 22
VIII. Arabinosyladenine (ara-A), Originally Conceived as an Antitumor Agent, the First Antiviral Drug Licensed and Used for Systemic Treatment 23
IX. Acyclovir: The Start of the Selective Antiviral Chemotherapy Era, and Still the ``Gold Standard´´ for HSV Therapy 25
X. Anti-influenza Virus Therapy: A First Attempt (DRB), Followed by a Second (Amantadine) and a Third Attempt (Neuraminidase Inhibitors) 27
XI. Ribavirin and Interferon, Two ``Old-Timers´´, Joining Forces in the Treatment of a Relatively New Disease, Hepatitis C 29
XII. (S)-9-(2,3-Dihydroxypropyl)adenine (DHPA), the First Acyclic Adenosine Analog, Leading to S-Adenosylhomocysteine (SAH) Hydrol Inhibitors as Broad-Spectrum Antiviral Agents 30
XIII. (S)-9-(2,3-Dihydroxypropyl)adenine (DHPA) Leading to the First Acyclic Nucleoside Phosphonate, (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)Adenine (HPMPA), As a Broad-Spectrum Antiviral Agent 32
XIV. 9-(2-Phosphonylmethoxyethyl)adenine (PMEA), the Sister Compound of HPMPA 33
XV. From PMEA (Adefovir) to PMPA (tenofovir): It All Depends on the Substitution of a Methyl Group for a Hydrogen 35
XVI. Suramin, the First Antiviral Drug Ever Shown to Inhibit HIV Infection Both in vitro and in vivo 36
XVII. The Nucleoside Reverse Transcriptase Inhibitors (NRTIs) with Azidothymidine (AZT) as the Starting Point 37
XVIII. The Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), with the HEPT and TIBO Derivatives as the Starting Point 39
XIX. The HIV Protease Inhibitors (PIs), Hailed From Their Inception, as Resulting from rational design 41
XX. New HIV Inhibitors, Targeted at Either Fusion (Enfuvirtide), Coreceptor usage (maraviroc), or Integrase (Raltegravir) 47
XXI. Conclusion 49
Acknowledgment 50
References 50
Chapter 2: Use of Animal Models to Understand the Pandemic Potential of Highly Pathogenic Avian Influenza Viruses 62
I. Introduction 63
II. Influenza A Virus Subtypes and Host Range 64
III. Avian Influenza A Virus in Humans 67
IV. Use of the Mouse Model to Study Influenza Virus Pathogenesis 70
A. Mouse model for human influenza A virus pathogenesis 70
B. Mouse model for H5N1 virus pathogenesis 72
C. Mouse model for H7 virus pathogenesis 74
D. Gene knockout mice in the study of avian influenza 75
E. Tropism of avian influenza viruses 77
V. Use of the Ferret Model to Study Influenza Virus Pathogenesis 78
A. Ferret model for human influenza A virus pathogenesis 78
B. Ferret model for H5N1 virus pathogenesis 79
C. Ferret model for H7 virus pathogenesis 80
D. Transmissibility of avian influenza viruses 81
VI. Molecular Basis of Avian Influenza Pathogenesis 82
A. Hemagglutinin cleavage site 83
B. Surface glycoproteins (HA and NA) 84
C. Polymerase complex 85
D. PB2 protein 86
E. PB1-F2 protein 88
F. NS1 protein 88
VII. Conclusions 89
Acknowledgments 91
References 91
Chapter 3: Virus Versus Host Cell Translation: Love and Hate Stories 106
I. Introduction 110
II. Regulation Prior to Translation 111
A. Editing 111
1. Editing by nucleotide modification 111
2. Editing by nucleotide addition 113
B. Splicing 115
C. Subgenomic RNA synthesis 117
III. Initiation of Translation 118
A. Cap-dependent initiation 118
B. Closed-loop model or circularization 119
C. VPg and initiation 122
D. IRES-directed initiation 123
E. Non-AUG initiation codons 126
F. Multiple reading frames 129
1. Leaky scanning 129
a. In-frame initiation 130
b. Overlapping ORFs 130
2. Reinitiation 132
3. Shunting 134
G. Modification of cell factors involved in initiation 135
1. Phosphorylation of eIF2alpha 136
2. Modification of eIF4E and 4E-BP 138
a. Dephosphorylation of eIF4E and of 4E-BP1 139
b. Phosphorylation of eIF4E and 4E-BP1 141
3. Modification of eIF4G 141
a. Cleavage of eIF4G 141
b. Phosphorylation of eIF4G 142
4. Cleavage of PABP 143
5. Substitution of PABP 143
6. Cleavage of PBCP2 144
IV. Elongation of Translation 144
A. Frameshift 144
B. Modification of elongation factors 147
V. Termination of Translation 148
A. Readthrough 148
B. Suppressor tRNAs 152
1. Suppressors of UAG/UAA codons 152
2. Suppressors of UGA codons 152
C. Binding of release factors 153
VI. Conclusions 153
Acknowledgments 154
References 154
Index 178