Front Cover

Retrovirus-Cell Interactions

Retrovirus-Cell Interactions

Copyright

Dedication

Contents

List of Contributors

Author Biographies

CHAPTER 1

CHAPTER 2

CHAPTER 3

CHAPTER 4

CHAPTER 5

CHAPTER 6

CHAPTER 7

CHAPTER 8

CHAPTER 9

CHAPTER 10

CHAPTER 11

CHAPTER 12

CHAPTER 13

CHAPTER 14

Preface

Introduction

REFERENCES

1 - Retrovirus Receptor Interactions and Entry

ENVELOPE GLYCOPROTEINS: DOMAIN STRUCTURE

RETROVIRUS ENTRY RECEPTORS

VIRUS ATTACHMENT

THE BASICS OF MEMBRANE FUSION

DO RECEPTOR INTERACTIONS CONTRIBUTE TO THE ENVELOPE PROTEINS FUNCTIONS THAT DRIVE ENTRY?

The Triggers

Conserved Motifs in Envelope Proteins Are Critical to Regulation of Fusion

Regulation by Control of the Conformation of Surface Subunit

Regulation by Control of Disulfide Bond Isomerization and Surface Subunit Conformation

Lentiviruses: Receptor-Triggered Conformational Changes in the Surface Subunit

Gammaretroviruses: Receptor- and Cellular Protease–Driven Disulfide Bond Isomerization

Alpharetroviruses: Receptor- and Low pH-Driven Disulfide Bond Isomerization

DO ENV–RECEPTOR INTERACTIONS CONTRIBUTE TO PATHOGENESIS?

CD4+ T-Cell Depletion and AIDS

Neurological Damage and HAM/TSP

Mutations That Adapt Virus to Low Receptor Levels Can Also Increase Pathogenicity

Envelope Protein–Driven Neoplasia in Betaretrovirus Infection

HOST DEFENSES THAT INHIBIT RETROVIRAL ENTRY ALSO DRIVE ENVELOPE PROTEIN VARIATION

Challenges in Vaccine Development

Interferon-Induced Transmembrane Proteins and Envelope Proteins Variation

COEVOLUTION OF VIRUS AND RECEPTOR

CAPTURED RETROVIRAL ENVELOPE PROTEINS IN THE DEVELOPMENT OF MAMMALIAN PLACENTA AND MALE MUSCLE MASS

REFERENCES

2 - Cellular Factors That Regulate Retrovirus Uncoating and Reverse Transcription

A BRIEF DESCRIPTION OF EARLY EVENTS OF INFECTION

MONITORING THE COURSE OF INFECTION IN EARLY STAGES

Monitoring Viral Nucleic Acids

Monitoring Incoming Viral Proteins

Imaging

HOST FACTORS PROMOTING EARLY EVENTS OF INFECTION

Breaking and Entering: Subcortical Actin

Factors Affecting Reverse Transcription

Cytoskeleton and Motors: Trafficking

Cyclophilin A, a Host Factor Binding Capsid

Modifications of Viral Proteins During Infection

HOST FACTORS RESTRICTING INFECTION IN EARLY STAGES OF INFECTION

Fv1, a Gene for Resistance to the Friend Leukemia Virus

TRIM5α, a Major Postentry Block

TRIM-Cyp: Evolution of a Restriction Factor by Gene Fusion

Mov10

Lv2: An Entry-Specific Block

APOBECs, the Cytidine Deaminases

SAMHD1, a Nucleotidase

MX2, Another Factor Targeting Capsid

SUN2

More Restriction Factors?

SENSING AND RESPONDING TO INFECTION: INNATE IMMUNITY

TRIM5α as Sensor

RIG-I and MDA5 as Retroviral Sensors

cGAS Involvement in Sensing Infection

IFI16, a DNA Sensor

TREX1, a Nuclease

APPLICATIONS FOR THERAPY

CONCLUSIONS: PARTING WORDS

REFERENCES

3 - Nucleoporins in Retroviral Replication: What’s Nup Got to Do with It?

NUCLEAR PORE COMPLEXES, NUCLEOPORINS, AND NUCLEOCYTOPLASMIC TRANSPORT

NUCLEOPORINS IMPLICATED IN RETROVIRAL REPLICATION

Normal Cellular Functions of the Nup358/RanBP2 Nuclear Pore Complex Protein

Functions of Nu358/RanBP2 in Retroviral Replication

Normal Cellular Functions of the Nup214/CAN Nuclear Pore Complex Protein

Functions of Nup214/CAN in Retroviral Replication

Normal Cellular Functions of the Nup98 Nuclear Pore Complex Protein

Functions of Nup98 in Retroviral Replication

Normal Cellular Functions of the Nup85 and Nup160 Components of the Nup107–160 Nuclear Pore Complex

Functions of the Nup107–160 Complex (Y-Complex) during Retroviral Replication

Normal Cellular Functions of the Nup62 Nuclear Pore Complex Protein

Functions of Nup62 in Retroviral Replication

Normal Cellular Functions of the Nup155 Nuclear Pore Complex Protein

Functions of Nup155 in Retroviral Replication

Normal Cellular Functions of the Nup153 Nuclear Pore Complex Protein

Functions of Nup153 in Retroviral Replication

Normal Cellular Functions of the Tetratricopeptide Repeat Nuclear Pore Complex Protein

Functions of Tetratricopeptide Repeat in Retroviral Replication

CAUTION: DEPLETION OF ANY SINGLE MULTIFUNCTIONAL NUP CAN MODIFY OVERALL NPC ARCHITECTURE

THE IMPORTANCE OF FG-REPEAT NUPS TO DISEASE

VIRUSES COMMONLY CAUSE THE DISPLACEMENT OF FG–NUPS TO REMODEL NPCS

ACKNOWLEDGMENTS

REFERENCES

4 - Virus–Host Interactions in Retrovirus Integration

INTRODUCTION

INTEGRASE-INTERACTING PROTEINS

LENTIVIRUSES

LENS EPITHELIUM–DERIVED GROWTH FACTOR/P75

HEPATOMA-DERIVED GROWTH FACTOR LIKE 2 (HDGFL2)

GAMMARETROVIRUSES

BROMODOMAIN AND EXTRA-TERMINAL DOMAIN PROTEINS

DELTARETROVIRUSES

B′-PROTEIN PHOSPHATASE 2A (PP2A)

GAG-INTERACTING PROTEINS

HIV-1 CA–INTERACTING PROTEINS

FOAMY VIRUS

ALLOSTERIC IN INHIBITORS THAT TARGET THE LEDGF/P75–IN INTERACTION

CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

5 - Transcriptional Control and Latency of Retroviruses

INTRODUCTION

RETROVIRAL INTEGRATION OCCURS AT TRANSCRIPTIONALLY ACTIVE SITES IN HOST GENOME

TRANSCRIPTIONAL REGULATION BY ENDOGENOUS RETROVIRUSES

Retroviral Elements Are Prominent in All Jawed Vertebrate Genomes

Endogenous Retroviruses Can Function as Long-Range Transcriptional Enhancers

Endogenous Retroviruses Regulate the Potency of Stem Cells

RETROVIRAL GENOME COMPLEXITY CONFERS A BENEFIT FOR TRANSCRIPTIONAL REGULATION

Transcriptional Regulation in Simple Retroviruses

Retroviral Capture of Cellular Genes for Transcription Factors or Signaling Kinases

Retroviral Use of Hormone Response Elements in Long Terminal Repeat Enhancer

Transcriptional Silencing of Simple Retroviruses

Complex Retroviruses Encode Transactivator Proteins

TRANSCRIPTIONAL CONTROL OF HIV-1

Clinical Importance of HIV-1 Proviral Transcription

HIV-1 5′ Long Terminal Repeat Contains the Viral Promoter and Enhancer

RNA Polymerase II Transcriptional Initiation of the HIV-1 Provirus

HIV-1 Tat Activates RNA Polymerase II Elongation

Tat and P-TEFb

CDK11 and HIV-1 3′ End Processing

HIV-1 LATENT INFECTION

Establishment of Latent Infection

Maintenance of Latent Infection

Reactivation of Latent Virus

FUTURE RESEARCH OF RETROVIRAL TRANSCRIPTION

HIV-1 Latency and the Need for a Functional Cure

Endogenous Retroviruses in Stem Cells and Cancer

ACKNOWLEDGMENTS

REFERENCES

6 - Teetering on the Edge: The Critical Role of RNA Processing Control During HIV-1 Replication

INTRODUCTION

ROLE OF HNRNPS IN THE REGULATION OF HIV-1 RNA PROCESSING

ROLE OF SR PROTEINS IN THE REGULATION OF HIV-1 RNA PROCESSING

MANIPULATION OF HIV-1 RNA PROCESSING WITH SMALL MOLECULES

ACKNOWLEDGMENTS

REFERENCES

7 - Cellular RNA Helicases Support Early and Late Events in Retroviral Replication

RNA HELICASE AND RETROVIRUSES IN THE ADVENT OF “OMICS TECHNOLOGY”

EARLY EVENTS: REVERSE TRANSCRIPTION AND INTEGRATION

DHX9/RNA HELICASE A ACTIVITY IN THE GENOMIC RNP

MOV10 ACTIVITY IN VIRIONS REMAINS UNDEFINED

LATE EVENTS: PROVIRUS TRANSCRIPTION, PRIMARY RNA PROCESSING, EXPORT, TRANSLATION, FORMATION OF GENOMIC RNP

DHX9, Bridging RNA Polymerase to Transcription Coactivators

Shuttling RNA Helicase in Nucleocytoplasmic Transport of Retroviral RNA

NUCLEAR CAP–BINDING PROTEINS AND RNA HELICASE: TRANSLATION EVADING NONSENSE RNA–MEDIATED DECAY

STEADY-STATE TRANSLATION: SWITCHING 5′CAP–BINDING PROTEINS TO GAIN EIF4E

THERAPEUTIC TARGETING AT THE INTERFACE OF RNA HELICASE AND COGNATE RETROVIRAL RNA

REFERENCES

8 - Role of Host Factors in the Subcellular Trafficking of Gag Proteins and Genomic RNA Leading to Virion Assembly

INTRODUCTION

NUCLEAR EXPORT OF VIRAL RNAS

Unspliced Viral RNA Export in Simple Retroviruses

The Constitutive Transport Element of MMTV

Export of Unspliced RNA in Rous Sarcoma Virus

Spumaretrovirus RNA Nuclear Export

RETROVIRAL GENOME TRAFFICKING IN THE CYTOPLASM

Relationship Between Viral RNA Export and Virus Assembly

Transport of Unspliced Viral RNA Through the Cytoplasm to the Assembly Site

Dimerization of Retroviral Genomic RNA

RETROVIRAL GAG PROTEIN TRAFFICKING

Nuclear Trafficking of Retroviral Gag Proteins

Foamy Virus Gag Association With Chromatin

Transport of Gag Proteins in the Cytoplasm

Role of Cytoskeletal Proteins and Microtubule-Organizing Center in Gag Transport

Multivesicular Bodies and Endosomal Proteins in Gag Trafficking

Role of Myristoylation and Lipid Binding in Gag Membrane Targeting

Multivesicular Body and Endosomal Sorting Complexes Required for Transport Pathway Interactions With Gag Late Domains

Nedd4 and E3 Ubiquitin Ligases

Tsg101 as a Central Player in Wide Range of Gag Late Domain Interactions

Alix/AIP-1 Interactions With HIV Gag Proteins

Late Domains in EIAV, MLV, and Foamy Virus Gag Proteins

Endophilin 2 in Murine Leukemia Virus Gag Trafficking

Association of Gag With tRNA Synthetases

FACTORS THAT INTERACT WITH GAG OR VIRAL RNA TO RESTRICT VIRUS REPLICATION

Host Restriction Factors That Interfere With Gag Functions Early or Late in Replication

CONCLUDING REMARKS

ACKNOWLEDGMENTS

REFERENCES

9 - Tumor Suppressor Gene 101: A Virus’ Multifunctional Conduit to the ESCRT Trafficking Machinery

INTRODUCTION

The Endosomal Sorting Complex Required for Transport Machinery

ESCRT-0

ESCRT-I

ESCRT-II

ESCRT-III

Endosomal Sorting Complexes Required for Transport Participation in Cellular Processes

Endosomal Sorting Complexes Required for Transport Participation in Virus Budding

TUMOR SUPPRESSOR GENE 101 STRUCTURE

Tsg101-UEV Domain

Tsg101-UEV PTAP-Binding Pocket

Tsg101-UEV Ub-Binding Pocket

Ub- and PTAP-Binding Pockets: Is There Cross Talk?

TUMOR SUPPRESSOR GENE 101 PARTICIPATION

Tumor Suppressor Gene 101 Participation in the Cellular Endocytic Pathway

Tumor Suppressor Gene 101 Participation in Virus Budding

CELLULAR FACTORS THAT WORK WITH TUMOR SUPPRESSOR GENE 101

Convergence of Tsg101-Ub-Nedd4-Alix Participation

TUMOR SUPPRESSOR GENE 101 ROLE IN BUDDING OF OTHER VIRUSES

QUESTIONS REMAINING

ACKNOWLEDGMENTS

REFERENCES

10 - The Role of Lipids in Retroviral Replication

INTRODUCTION

Composition of Cellular Membranes

Composition of Viral Membranes

Membrane Microdomains

LIPIDS IN RETROVIRAL ENTRY

Role of Cholesterol in Retroviral Entry

Role of Sphingolipids in Retroviral Entry

Role of Phospholipids in Retroviral Entry

RETROVIRAL ASSEMBLY

Trafficking of Gag and Sites of Retroviral Assembly

Gag–Membrane Interactions

Lipids in Retroviral Assembly

Role of Cholesterol in Retroviral Assembly

Role of PI(4,5)P2 in Retroviral Assembly

Gag Binding to Giant Unilamellar Vesicles

LIPIDS IN RETROVIRAL CELL–CELL TRANSFER

Retroviral Accessory Proteins and Lipid Microdomains

INHIBITION OF RETROVIRAL REPLICATION WITH LIPID-MODIFYING AGENTS

Cholesterol Modifying Agents

Inhibitors of Sphingolipid Synthesis

CONCLUDING REMARKS

REFERENCES

11 - Cellular Immune Responses to Retroviruses

INTRODUCTION

STEPS OF THE RETROVIRUS INFECTION PATHWAY TARGETED BY THE HOST INTRINSIC/INNATE RESPONSE

HOST PATHWAYS IMPLICATED IN CELLULAR CONTROL OF RETROVIRUS INFECTION

SUBVERSION OF CELLULAR IMMUNE RESPONSES BY RETROVIRUSES

CONCLUSIONS

REFERENCES

12 - Noncoding RNAs in Retrovirus Replication

INTRODUCTION

HOST RNAS PACKAGED INTO VIRIONS

Transfer RNAs

7SL RNA

U Small Nuclear RNA

Y RNA

Vault RNA

High-Throughput RNA-Sequencing Studies

LONG NONCODING RNA AND ENDOGENOUS RETROVIRUSES

NRON: HIV-1

NEAT1: HIV-1

Large Intergenic RNA–p21: HIV-1

Antisense Protein RNA: HIV-1

Long Noncoding RNA 00173: HIV-1

ASP RNA: HTLV-1

Bic: ALV and His-1: MLV

Endogenous Retroviruses

FUNCTIONAL TRANSACTIVATING RESPONSE ELEMENT RNAS

RNA INTERFERENCE AND MIRNAS

RNAi, miRNA, and siRNA Production

Cellular MicroRNAs Made in Response to Viral Infections

Viral MicroRNAs Encoded Within Genomes

Viral Suppressors of RNA Silencing

THERAPEUTICS

CONCLUDING REMARKS

ACKNOWLEDGMENTS

REFERENCES

13 - Cellular Control of Endogenous Retroviruses and Retroelements

INTRODUCTION

BACKGROUND

Long Terminal Repeat Retrotransposons and Endogenous Retroviruses Fig. 13.1

Non-Long Terminal Repeat Retrotransposons

Long Interspersed Elements

Short Interspersed Elements

Chimeric Short Interspersed Elements

Pseudogenes

ACTIVITY

Frequencies of Retrotransposition

Retroelement Activities and Impacts

CONTROL OF RETROELEMENT EXPRESSION

Retroelement Transcription Patterns Favor Self-Preservation

Regulation of Retroelements in Somatic Cells by RNA Interference Fig. 13.2

Regulation of Retroelements in Germline and Embryonic Stem Cells

Sequence-Specific Suppression of Retroelements

Neuronal Activity of Retroelements

Roles for Retroelements in Cancer Initiation and Progression

REGULATION OF RETROELEMENTS BY THE INNATE IMMUNE SYSTEM

Regulation of Innate Immunity by Endogenous Retrovirus Sequences Fig. 13.3

Sensing of Retroelements by Innate Immunity

Direct Control of Retroelements by Innate Immunity

PERSPECTIVES

ACKNOWLEDGMENTS

REFERENCES

14 - Strategies to Discover Novel Cellular Factors Involved in Retrovirus Replication

INTRODUCTION

IDENTIFYING PROTEIN–PROTEIN INTERACTIONS IN RETROVIRUSES USING TWO-HYBRID SCREENS

Using Gag Proteins as Bait

Using Integrase as Bait

Additional Retroviral Proteins Used as Bait

MASS SPECTROMETRY APPROACHES TO DISCOVERY OF RETROVIRUS–CELL PROTEIN–PROTEIN INTERACTIONS

Mass Spectrometry to Identify Proteins Packaged Into Virus Particles

Mass Spectrometry to Identify Host Proteins Interacting With HIV-1 Proteins

Affinity Purification Approaches

Liquid Chromatography Coupled to Tandem Mass Spectrometry

Multidimensional Protein Identification Technology Mass Spectrometry

MASS SPECTROMETRY USING VIRAL DNA AS BAIT

HIV-1 5′ Untranslated Regions as Bait

MASS SPECTROMETRY USING VIRAL RNA AS BAIT

HIV-1 Subgenomic RNAs as Bait

Retroviral 5′Untranslated Regions as Bait

Full-Length HIV-1 RNA Used as Bait

RNA INTERFERENCE AND GENOME-WIDE SCREENS TO ASSESS THE CONTRIBUTION OF HOST FACTORS TO VIRUS REPLICATION

Small Interfering RNA Screens

Short Hairpin RNA Screens

Metaanalysis of siRNA Screens in HIV-1 Replication

Targeted RNAi Screens

Genome-Wide Analysis of Retrotransposition in Yeast

HOST GENOME EDITING USING CRISPR/CAS-9 TO FIND RETROVIRUS DEPENDENCY GENES

GAIN-OF-FUNCTION GENETIC APPROACHES USING CDNA OVEREXPRESSION SCREENS

IDENTIFICATION OF CELLULAR RNAS THAT INTERACT WITH RETROVIRUSES

Host RNAs Packaged Into Retrovirus Particles

RNA Sequencing Techniques

CONCLUDING REMARKS

ACKNOWLEDGMENTS

REFERENCES

Index

A

B

C

D

E

F

G

H

I

J

K

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M

N

O

P

R

S

T

U

V

X

Y

Z

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