Retrovirus-Cell Interactions

Leslie Parent

• Publisher: Academic Press
• Year: 2018
• Print ISBN: 9780128111857
• eBook ISBN: 9780128111932
• Topic: Biological Sciences
• Subtopic: Infectious Diseases
• Index: Biological Sciences

Retrovirus-Cell Interactions provides an up-to-date review of the interactions between retroviruses and the cells they infect, offering a comprehensive understanding of how retroviruses hijack cellular factors to facilitate virus replication. Drugs targeting viral enzymes have been developed to treat HIV; the next challenge is to inhibit virus-cell interactions as next generation treatment strategies. Organized according to the retrovirus' replication cycle, this book does not focus exclusively on HIV, but rather includes important findings in other retroviral systems, including animal retroviruses, retrotransposons, and endogenous retroelements to allow broad comparisons on important commonalities and differences. - Provides a valuable starting point for people who want to develop a detailed understanding of retroviral replication - Includes future-thinking strategies, such as next-generation treatment and anti-retroviral therapeutics - Features important commonalities and differences among retroviral systems

Chapter 1

Retrovirus Receptor Interactions and Entry

Lorraine M. Albritton The University of Tennessee Health Science Center, Memphis, TN, United States

Abstract

This chapter describes the functional domains of retroviral envelope proteins, attributes of their host cell receptors, the native and postfusion structures of envelope proteins, virus attachment sites, and basic concepts of membrane fusion. It then uses these fundamental concepts to consider two variations in the conformational changes in the envelope proteins, how they impact the entry mechanisms and fusion triggers used by retroviruses, and the hallmark motifs that identify which mechanism a retrovirus uses. The final sections discuss the contribution of virus–host cell interactions to retroviral pathogenesis, challenges in creating broadly effective vaccines, coevolution of retroviruses and their entry receptors, and the impact of captured retroviral Env on mammalian evolution and development.

Keywords

Entry mechanism; Envelope glycoprotein; Fusion trigger; HIV vaccine; Membrane fusion; Placental development; Retrovirus entry; Six-helix bundle; Virus coevolution; Virus receptor

Chapter Outline

1. Envelope Glycoproteins: Domain Structure
2. Retrovirus Entry Receptors
3. Virus Attachment
4. The Basics of Membrane Fusion
5. Do Receptor Interactions Contribute to the Envelope Proteins Functions That Drive Entry?
   1. The Triggers
   2. Conserved Motifs in Envelope Proteins Are Critical to Regulation of Fusion
   3. Regulation by Control of the Conformation of Surface Subunit
   4. Regulation by Control of Disulfide Bond Isomerization and Surface Subunit Conformation
   5. Lentiviruses: Receptor-Triggered Conformational Changes in the Surface Subunit
   6. Gammaretroviruses: Receptor- and Cellular Protease–Driven Disulfide Bond Isomerization
   7. Alpharetroviruses: Receptor- and Low pH-Driven Disulfide Bond Isomerization
6. Do Env–Receptor Interactions Contribute to Pathogenesis?
   1. CD4+ T-Cell Depletion and AIDS
   2. Neurological Damage and HAM/TSP
   3. Mutations That Adapt Virus to Low Receptor Levels Can Also Increase Pathogenicity
   4. Envelope Protein–Driven Neoplasia in Betaretrovirus Infection
7. Host Defenses That Inhibit Retroviral Entry Also Drive Envelope Protein Variation
   1. Challenges in Vaccine Development
   2. Interferon-Induced Transmembrane Proteins and Envelope Proteins Variation
8. Coevolution of Virus and Receptor
9. Captured Retroviral Envelope Proteins in the Development of Mammalian Placenta and Male Muscle Mass
10. References

Interactions that occur during entry into naïve host cells are basic determinants of the host range and cell tropism of each retrovirus. The principal players are the retroviral envelope proteins (Env) and their host cell receptors. This chapter briefly describes the functional domains of Env, attributes of their receptors, and the basics of membrane fusion. It then uses these fundamental concepts to consider two questions. What role do Env and host cell receptor interactions play in entry? Do these interactions contribute to viral pathogenesis? The final sections discuss challenges in creating vaccines, coevolution of retroviruses and their entry receptors, and the impact of captured retroviral Env on mammalian evolution and development.

Envelope Glycoproteins: Domain Structure

Retroviral genomes contain a single env gene that is expressed from a spliced mRNA. In the host cell endoplasmic reticulum, newly synthesized Env associate with two additional molecules to generate a trimer. A host protease in the Golgi apparatus cleaves each Env protomer into two subunits, the surface subunit (SU) and the transmembrane subunit (TM), and they mature into native Env trimers that are incorporated into the membrane of new virus particles (Fig. 1.1A). Env trimers provide the only productive interactions with a potential host cell–specific virus attachment to entry receptors and fusion of viral and cellular membranes. The binding sites for the entry receptors are in SU and the membrane fusion activities belong to TM.

The domain structure of all but the epsilonretrovirus and spumavirus Env occurs in two arrangements and each correlates with a basic entry mechanism. The hallmarks of the first mechanism are a covalent bond between a central CXXC motif in SU and a C(X)₆CCF motif in TM, an N-terminal histidine motif in SU, and a conserved HR1 trimerization domain and relatively short HR2 in their TM. Type D betaretroviruses and alpha-, delta-, and gammaretroviruses have these features (Fig. 1.1B). Lentiviruses and the betaretroviruses, including mouse mammary tumor virus (MMTV), jaagsiekte sheep retrovirus (JSRV), and enzootic nasal tumor virus (ENTV), use the second mechanism. Its hallmarks are a lack of covalent bond between SU and TM and a C(X)_5-7C motif with long HR2 in TM (Fig. 1.1C).

Gamma-, beta-, and deltaretroviruses maintain receptor-binding sequences within an N-terminal receptor-binding domain (RBD), which is followed by a short flexible region that is proline-rich and a C-terminal domain containing the CXXC motif that bonds with TM. Soluble forms of these RBD are active and useful in identifying entry receptors and receptor-binding sites (Manel et al., 2003a; Kim et al., 2004; Kinet et al., 2007). In contrast, the receptor-binding sequences of SU from lentiviruses, alpha-, epsilonretroviruses, and spumaviruses are distributed across their length; there are no discrete N- and C-terminal domains within SU (Sun et al., 2008; Melder et al., 2015). These genera also vary in the size and function of the cytoplasmic tail domains on TM.

Figure 1.1 (A) Sequential synthesis, trimerization of HR1, and host protease processing of envelope proteins (Env) at the KXK/RR site create fusion-competent trimers for assembly into virions. The domain structure of Env occurs in two functional forms that differ primarily in the presence (B) or absence (C) of a covalent bond between SU and TM. Dotted connectors indicate disulfide bonds. KXK/RR, SPHQ, CXXC, VHLL, C(X)₁₂C, C(X)₆CCF, and C(X)_5-7C denote functional motifs using the single-letter amino acid code. Variable regions are denoted by VR, vr, or V followed by a letter or number. The open circle and asterisks denote segments of HIV-1 SU that interact with CD4. hr1 and hr2 denote the host range sequences of alpharetrovirus Env. CTD, C-terminal domain; ER, endoplasmic reticulum.; HR1 and 2, heptad repeat 1 and 2; MPER, membrane proximal external region; PRR, proline-rich region; RBD, receptor-binding domain; SP, signal peptide; SU, surface subunit; TM, transmembrane subunit.

SUs contain regions that vary considerably between ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Notices
• Dedication
• List of Contributors
• Author Biographies
• Preface
• Introduction
• Chapter 1. Retrovirus Receptor Interactions and Entry
• Chapter 2. Cellular Factors That Regulate Retrovirus Uncoating and Reverse Transcription
• Chapter 3. Nucleoporins in Retroviral Replication: What’s Nup Got to Do with It?
• Chapter 4. Virus–Host Interactions in Retrovirus Integration
• Chapter 5. Transcriptional Control and Latency of Retroviruses
• Chapter 6. Teetering on the Edge: The Critical Role of RNA Processing Control During HIV-1 Replication
• Chapter 7. Cellular RNA Helicases Support Early and Late Events in Retroviral Replication
• Chapter 8. Role of Host Factors in the Subcellular Trafficking of Gag Proteins and Genomic RNA Leading to Virion Assembly
• Chapter 9. Tumor Suppressor Gene 101: A Virus’ Multifunctional Conduit to the ESCRT Trafficking Machinery
• Chapter 10. The Role of Lipids in Retroviral Replication
• Chapter 11. Cellular Immune Responses to Retroviruses
• Chapter 12. Noncoding RNAs in Retrovirus Replication
• Chapter 13. Cellular Control of Endogenous Retroviruses and Retroelements
• Chapter 14. Strategies to Discover Novel Cellular Factors Involved in Retrovirus Replication
• Index