Showing papers in "Annual Review of Virology in 2016"

Structure, Function, and Evolution of Coronavirus Spike Proteins.

Abstract: The coronavirus spike protein is a multifunctional molecular machine that mediates coronavirus entry into host cells. It first binds to a receptor on the host cell surface through its S1 subunit and then fuses viral and host membranes through its S2 subunit. Two domains in S1 from different coronaviruses recognize a variety of host receptors, leading to viral attachment. The spike protein exists in two structurally distinct conformations, prefusion and postfusion. The transition from prefusion to postfusion conformation of the spike protein must be triggered, leading to membrane fusion. This article reviews current knowledge about the structures and functions of coronavirus spike proteins, illustrating how the two S1 domains recognize different receptors and how the spike proteins are regulated to undergo conformational transitions. I further discuss the evolution of these two critical functions of coronavirus spike proteins, receptor recognition and membrane fusion, in the context of the corresponding fu...

Viruses as Winners in the Game of Life

Abstract: Viruses are the most abundant and the most diverse life form. In this meta-analysis we estimate that there are 4.80×1031 phages on Earth. Further, 97% of viruses are in soil and sediment-two underinvestigated biomes that combined account for only ∼2.5% of publicly available viral metagenomes. The majority of the most abundant viral sequences from all biomes are novel. Our analysis drawing on all publicly available viral metagenomes observed a mere 257,698 viral genotypes on Earth-an unrealistically low number-which attests to the current paucity of viral metagenomic data. Further advances in viral ecology and diversity call for a shift of attention to previously ignored major biomes and careful application of verified methods for viral metagenomic analysis.

Human Cytomegalovirus Latency: Approaching the Gordian Knot.

Abstract: Herpesviruses have evolved exquisite virus-host interactions that co-opt or evade a number of host pathways to enable the viruses to persist. Persistence of human cytomegalovirus (CMV), the prototypical betaherpesvirus, is particularly complex in the host organism. Depending on host physiology and the cell types infected, CMV persistence comprises latent, chronic, and productive states that may occur concurrently. Viral latency is a central strategy by which herpesviruses ensure their lifelong persistence. Although much remains to be defined about the virus-host interactions important to CMV latency, it is clear that checkpoints composed of viral and cellular factors exist to either maintain a latent state or initiate productive replication in response to host cues. CMV offers a rich platform for defining the virus-host interactions and understanding the host biology important to viral latency. This review describes current understanding of the virus-host interactions that contribute to viral latency and reactivation.

The Genus Tospovirus: Emerging Bunyaviruses that Threaten Food Security.

Abstract: The genus Tospovirus is unique within the family Bunyaviridae in that it is made up of viruses that infect plants. Initially documented over 100 years ago, tospoviruses have become increasingly important worldwide since the 1980s due to the spread of the important insect vector Frankliniella occidentalis and the discovery of new viruses. As a result, tospoviruses are now recognized globally as emerging agricultural diseases. Tospoviruses and their vectors, thrips species in the order Thysanoptera, represent a major problem for agricultural and ornamental crops that must be managed to avoid devastating losses. In recent years, the number of recognized species in the genus has increased rapidly, and our knowledge of the molecular interactions of tospoviruses with their host plants and vectors has expanded. In this review, we present an overview of the genus Tospovirus with particular emphasis on new understandings of the molecular plant-virus and vector-virus interactions as well as relationships among genu...

A Cap-to-Tail Guide to mRNA Translation Strategies in Virus-Infected Cells

Abstract: Although viruses require cellular functions to replicate, their absolute dependence upon the host translation machinery to produce polypeptides indispensable for their reproduction is most conspicuous. Despite their incredible diversity, the mRNAs produced by all viruses must engage cellular ribosomes. This has proven to be anything but a passive process and has revealed a remarkable array of tactics for rapidly subverting control over and dominating cellular regulatory pathways that influence translation initiation, elongation, and termination. Besides enforcing viral mRNA translation, these processes profoundly impact host cell-intrinsic immune defenses at the ready to deny foreign mRNA access to ribosomes and block protein synthesis. Finally, genome size constraints have driven the evolution of resourceful strategies for maximizing viral coding capacity. Here, we review the amazing strategies that work to regulate translation in virus-infected cells, highlighting both virus-specific tactics and the tremendous insight they provide into fundamental translational control mechanisms in health and disease.

The Structural Biology of Hepatitis B Virus: Form and Function.

Abstract: Hepatitis B virus is one of the smallest human pathogens, encoded by a 3,200-bp genome with only four open reading frames. Yet the virus shows a remarkable diversity in structural features, often with the same proteins adopting several conformations. In part, this is the parsimony of viruses, where a minimal number of proteins perform a wide variety of functions. However, a more important theme is that weak interactions between components as well as components with multiple conformations that have similar stabilities lead to a highly dynamic system. In hepatitis B virus, this is manifested as a virion where the envelope proteins have multiple structures, the envelope-capsid interaction is irregular, and the capsid is a dynamic compartment that actively participates in metabolism of the encapsidated genome and carries regulated signals for intracellular trafficking.

Properties and Functions of the Dengue Virus Capsid Protein

Abstract: Dengue virus affects hundreds of millions of people each year around the world, causing a tremendous social and economic impact on affected countries. The aim of this review is to summarize our current knowledge of the functions, structure, and interactions of the viral capsid protein. The primary role of capsid is to package the viral genome. There are two processes linked to this function: the recruitment of the viral RNA during assembly and the release of the genome during infection. Although particle assembly takes place on endoplasmic reticulum membranes, capsid localizes in nucleoli and lipid droplets. Why capsid accumulates in these locations during infection remains unknown. In this review, we describe available data and discuss new ideas on dengue virus capsid functions and interactions. We believe that a deeper understanding of how the capsid protein works during infection will create opportunities for novel antiviral strategies, which are urgently needed to control dengue virus infections.

Viruses and the Diversity of Cell Death.

Abstract: Cell death is a common outcome of virus infection. In some cases, cell death curbs virus replication. In others, cell death enhances virus dissemination and contributes to tissue injury, exacerbating viral disease. Three forms of cell death are observed following virus infection-apoptosis, necroptosis, and pyroptosis. In this review, I describe the core machinery needed for each of these forms of cell death. Using representative viruses, I highlight how distinct stages of virus replication initiate signaling pathways that elicit these forms of cell death. I also discuss viral strategies to overcome the deleterious effects of cell death on virus propagation and the consequences of cell death for host physiology.

Tombusvirus-Host Interactions: Co-Opted Evolutionarily Conserved Host Factors Take Center Court

Abstract: Plant positive-strand (+)RNA viruses are intracellular infectious agents that reorganize subcellular membranes and rewire the cellular metabolism of host cells to achieve viral replication in elaborate replication compartments. This review describes the viral replication process based on tombusviruses, highlighting common strategies with other plant and animal viruses. Overall, the works on Tomato bushy stunt virus (TBSV) have revealed intriguing and complex functions of co-opted cellular translation factors, heat shock proteins, DEAD-box helicases, lipid transfer proteins, and membrane-deforming proteins in virus replication. The emerging picture is that many of the co-opted host factors are from highly expressed and conserved protein families. By hijacking host proteins, phospholipids, sterols, and the actin network, TBSV exerts supremacy over the host cell to support viral replication in large replication compartments. Altogether, these advances in our understanding of tombusvirus-host interactions are broadly applicable to many other viruses, which also usurp conserved host factors for various viral processes.

Bats as Viral Reservoirs

Abstract: Bats are hosts of a range of viruses, including ebolaviruses, and many important human viral infections, such as measles and mumps, may have their ancestry traced back to bats. Here, I review viruses of all viral families detected in global bat populations. The viral diversity in bats is substantial, and viruses with all known types of genomic structures and replication strategies have been discovered in bats. However, the discovery of viruses is not geographically even, with some apparently undersampled regions, such as South America. Furthermore, some bat families, including those with global or wide distributions such as Emballonuridae and Miniopteridae, are underrepresented on viral databases. Future studies, including those that address these sampling gaps along with those that develop our understanding of viral-host relationships, are highlighted.

The Strange, Expanding World of Animal Hepaciviruses

Abstract: Hepaciviruses and pegiviruses constitute two closely related sister genera of the family Flaviviridae In the past five years, the known phylogenetic diversity of the hepacivirus genera has absolutely exploded What was once an isolated infection in humans (and possibly other primates) has now expanded to include horses, rodents, bats, colobus monkeys, cows, and, most recently, catsharks, shedding new light on the genetic diversity and host range of hepaciviruses Interestingly, despite the identification of these many animal and primate hepaciviruses, the equine hepaciviruses remain the closest genetic relatives of the human hepaciviruses, providing an intriguing clue to the zoonotic source of hepatitis C virus This review summarizes the significance of these studies and discusses current thinking about the origin and evolution of the animal hepaciviruses as well as their potential usage as surrogate models for the study of hepatitis C virus

Modeling Viral Spread

Abstract: The way in which a viral infection spreads within a host is a complex process that is not well understood. Different viruses, such as human immunodeficiency virus type 1 and hepatitis C virus, have evolved different strategies, including direct cell-to-cell transmission and cell-free transmission, to spread within a host. To what extent these two modes of transmission are exploited in vivo is still unknown. Mathematical modeling has been an essential tool to get a better systematic and quantitative understanding of viral processes that are difficult to discern through strictly experimental approaches. In this review, we discuss recent attempts that combine experimental data and mathematical modeling in order to determine and quantify viral transmission modes. We also discuss the current challenges for a systems-level understanding of viral spread, and we highlight the promises and challenges that novel experimental techniques and data will bring to the field.

Climate Change and the Arboviruses: Lessons from the Evolution of the Dengue and Yellow Fever Viruses.

Abstract: The impact of anticipated changes in global climate on the arboviruses and the diseases they cause poses a significant challenge for public health. The past evolution of the dengue and yellow fever viruses provides clues about the influence of changes in climate on their future evolution. The evolution of both viruses has been influenced by virus interactions involving the mosquito species and the primate hosts involved in virus transmission, and by their domestic and sylvatic cycles. Information is needed on how viral genes in general influence phenotypic variance for important viral functions. Changes in global climate will alter the interactions of mosquito species with their primate hosts and with the viruses in domestic cycles, and greater attention should be paid to the sylvatic cycles. There is great danger for the evolution of novel viruses, such as new serotypes, that could compromise vaccination programs and jeopardize public health. It is essential to understand (a) both sylvatic and domestic c...

Nuclear Exodus: Herpesviruses Lead the Way

Abstract: Most DNA viruses replicate in the nucleus and exit it either by passing through the nuclear pores or by rupturing the nuclear envelope. Unusually, herpesviruses have evolved a complex mechanism of nuclear escape whereby nascent capsids bud at the inner nuclear membrane to form perinuclear virions that subsequently fuse with the outer nuclear membrane, releasing capsids into the cytosol. Although this general scheme is accepted in the field, the players and their roles are still debated. Recent studies illuminated critical mechanistic features of this enigmatic process and uncovered surprising parallels with a novel cellular nuclear export process. This review summarizes our current understanding of nuclear egress in herpesviruses, examines the experimental evidence and models, and outlines outstanding questions with the goal of stimulating new research in this area.

Genomic Analysis of Viral Outbreaks

Abstract: Genomic analysis is a powerful tool for understanding viral disease outbreaks. Sequencing of viral samples is now easier and cheaper than ever before and can supplement epidemiological methods by providing nucleotide-level resolution of outbreak-causing pathogens. In this review, we describe methods used to answer crucial questions about outbreaks, such as how they began and how a disease is transmitted. More specifically, we explain current techniques for viral sequencing, phylogenetic analysis, transmission reconstruction, and evolutionary investigation of viral pathogens. By detailing the ways in which genomic data can help us understand viral disease outbreaks, we aim to provide a resource that will facilitate the response to future outbreaks.

Unraveling the Mysterious Interactions Between Hepatitis C Virus RNA and Liver-Specific MicroRNA-122

Abstract: Many viruses encode or subvert cellular microRNAs (miRNAs) to aid in their gene expression, amplification strategies, or pathogenic signatures. miRNAs typically downregulate gene expression by binding to the 3′ untranslated region of their mRNA targets. As a result, target mRNAs are translationally repressed and subsequently deadenylated and degraded. Curiously, hepatitis C virus (HCV), a member of the Flaviviridae family, recruits two molecules of liver-specific microRNA-122 (miR-122) to the 5′ end of its genome. In contrast to the canonical activity of miRNAs, the interactions of miR-122 with the viral genome promote viral RNA accumulation in cultured cells and in animal models of HCV infection. Sequestration of miR-122 results in loss of viral RNA both in cell culture and in the livers of chronic HCV-infected patients. This review discusses the mechanisms by which miR-122 is thought to enhance viral RNA abundance and the consequences of miR-122–HCV interactions. We also describe preliminary findings fr...

Integrins as Herpesvirus Receptors and Mediators of the Host Signalosome

Abstract: The repertoire of herpesvirus receptors consists of nonintegrin and integrin molecules. Integrins interact with the conserved glycoproteins gH/gL or gB. This interaction is a conserved biology across the Herpesviridae family, likely directed to promote virus entry and endocytosis. Herpesviruses exploit this interaction to execute a range of critical functions that include (a) relocation of nonintegrin receptors (e.g., herpes simplex virus nectin1 and Kaposi's sarcoma-associated herpesvirus EphA2), or association with nonintegrin receptors (i.e., human cytomegalovirus EGFR), to dictate species-specific entry pathways; (b) activation of multiple signaling pathways (e.g., Ca2+ release, c-Src, FAK, MAPK, and PI3K); and (c) association with Rho GTPases, tyrosine kinase receptors, Toll-like receptors, which result in cytoskeletal remodeling, differential cell type targeting, and innate responses. In turn, integrins can be modulated by viral proteins (e.g., Epstein-Barr virus LMPs) to favor spread of transformed cells. We propose that herpesviruses evolved a multipartite entry system to allow interaction with multiple receptors, including integrins, required for their sophisticated life cycle.

Bugs Are Not to Be Silenced: Small RNA Pathways and Antiviral Responses in Insects

Abstract: Like every other organism on Earth, insects are infected with viruses, and they rely on RNA interference (RNAi) mechanisms to circumvent viral infections. A remarkable characteristic of RNAi is that it is both broadly acting, because it is triggered by double-stranded RNA molecules derived from virtually any virus, and extremely specific, because it targets only the particular viral sequence that initiated the process. Reviews covering the different facets of the RNAi antiviral immune response in insects have been published elsewhere. In this review, we build a framework to guide future investigation. We focus on the remaining questions and avenues of research that need to be addressed to move the field forward, including issues such as the activity of viral suppressors of RNAi, comparative genomics, the development of detailed maps of the subcellular localization of viral replication complexes with the RNAi machinery, and the regulation of the antiviral RNAi response.

Moving On Out: Transport and Packaging of Influenza Viral RNA into Virions

Abstract: Influenza A viruses bear an eight-segmented single-stranded negative-sense RNA genome that is replicated in the nucleus. Newly synthesized viral RNA (vRNA) segments are exported from the nucleus and transported to the plasma membrane for packaging into progeny virions. Influenza viruses exploit many host proteins during these events, and this is the portion of the viral life cycle when genetic reassortment among influenza viruses occurs. Reassortment among influenza A viruses allows viruses to expand their host range, virulence, and pandemic potential. This review covers recent studies on the export of vRNAs from the nucleus and their transport through the cytoplasm, progressive assembly, and packaging into progeny virus particles. Understanding these events and the constraints on genetic reassortment has implications for assessment of the pandemic potential of newly emerged influenza viruses, for vaccine production, for determination of viral fitness, and for identification of novel therapeutic targets.

The Discovery of Reverse Transcriptase

Abstract: In 1970 the independent and simultaneous discovery of reverse transcriptase in retroviruses (then RNA tumor viruses) by David Baltimore and Howard Temin revolutionized molecular biology and laid the foundations for retrovirology and cancer biology. In this historical review we describe the formulation of the controversial provirus hypothesis by Temin, which ultimately was proven by his discovery of reverse transcriptase in Rous sarcoma virus virions. Baltimore arrived at the same discovery through his studies on replication of RNA-containing viruses, starting with poliovirus and then moving to vesicular stomatitis virus, where he discovered a virion RNA polymerase. Subsequent studies of reverse transcriptase led to the elucidation of the mechanism of retrovirus replication, the discovery of oncogenes, the advent of molecular cloning, the search for human cancer viruses, and the discovery and treatment of HIV/AIDS.

Epstein-Barr Virus: The Path from Latent to Productive Infection.

Abstract: The intrinsic properties of different viruses have driven their study. For example, the capacity for efficient productive infection of cultured cells by herpes simplex virus 1 has made it a paradigm for this mode of infection for herpesviruses in general. Epstein-Barr virus, another herpesvirus, has two properties that have driven its study: It causes human cancers, and it exhibits a tractable transition from its latent to its productive cycle in cell culture. Here, we review our understanding of the path Epstein-Barr virus follows to move from a latent infection to and through its productive cycle. We use information from human infections to provide a framework for describing studies in cell culture and, where possible, the molecular resolutions from these studies. We also pose questions whose answers we think are pivotal to understanding this path, and we provide answers where we can.

Single-Cell Studies of Phage λ: Hidden Treasures Under Occam's Rug

Abstract: Studies over more than half a century have resulted in what some consider a complete narrative for the life cycle of bacteriophage λ. However, this narrative is only complete within the limited resolution offered by the traditional genetic and biochemical approaches that were used to create it. A recent series of studies performed at the single-cell and single-phage levels has revealed a wealth of previously unknown features. By pointing to many open questions, these new studies highlight the limitations of our current understanding of λ, but they also initiate the process of forming a more detailed and quantitative narrative for the system.

Epidemiology and Management of the 2013-16 West African Ebola Outbreak.

Abstract: The 2013-16 West African Ebola outbreak is the largest, most geographically dispersed, and deadliest on record, with 28,616 suspected cases and 11,310 deaths recorded to date in Guinea, Liberia, and Sierra Leone. We provide a review of the epidemiology and management of the 2013-16 Ebola outbreak in West Africa aimed at stimulating reflection on lessons learned that may improve the response to the next international health crisis caused by a pathogen that emerges in a region of the world with a severely limited health care infrastructure. Surveillance efforts employing rapid and effective point-of-care diagnostics designed for environments that lack advanced laboratory infrastructure will greatly aid in early detection and containment efforts during future outbreaks. Introduction of effective therapeutics and vaccines against Ebola into the public health system and the biodefense armamentarium is of the highest priority if future outbreaks are to be adequately managed and contained in a timely manner.

Transgenic Mouse Models of Tumor Virus Action

Abstract: Genetically engineered mice (GEMs) have provided valuable insights into the carcinogenic properties of various human tumor viruses, which, in aggregate, are etiologically associated with over 15% of all human cancers. This review provides an overview of seminal discoveries made through the use of GEM models for human DNA tumor viruses. Emphasis is placed on the discoveries made in the study of human papillomaviruses, Merkel cell carcinoma-associated polyomavirus, Epstein-Barr virus, and Kaposi's sarcoma-associated herpesvirus, because GEMs have contributed extensively to our understanding of how these DNA tumor viruses directly contribute to human cancers.

Rotavirus Strategies Against the Innate Antiviral System

Abstract: “Rotaviruses represent the most important etiological agents of acute, severe gastroenteritis in the young of many animal species, including humans.” This statement, variations of which are a common beginning in articles about rotaviruses, reflects the fact that these viruses have evolved efficient strategies for evading the innate immune response of the host and for successfully replicating in the population. In this review, we summarize what is known about the defense mechanisms that host cells employ to prevent rotavirus invasion and the countermeasures that these viruses have successfully developed to surpass cellular defenses. Rotaviruses use at least two viral multifunctional proteins to directly interact with, and prevent the activation of, the interferon system, and they use at least one other protein to halt the protein synthesis machinery and prevent the expression of most of the transcriptional antiviral program of the cell. Characterization of the confrontation between rotaviruses and their ho...

More than Meets the Eye: Hidden Structures in the Proteome.

Abstract: A central dogma of molecular biology is that the sequence of a protein dictates its particular fold and the fold dictates its function. Indeed, the sequence → structure → function hypothesis has been a guiding principle by which scientists approach molecular biology. Every student knows that the genome encodes information for the progression from primary sequence to secondary, tertiary, and ultimately quaternary structure. Yet with a growing number of proteins, a fifth level has been identified: rearrangement of existing structures into distinct forms. Recent observations indicate that replication of Ebola virus depends on this fifth level. We believe other viruses with compact genomes and rapid evolution under selective pressure will be a rich source of examples of polypeptides that rearrange to gain added functions. In this review, we describe mechanisms by which viral, prokaryotic, and eukaryotic polypeptides have adopted alternate structures to control or gain function.

The Language of Life.

Abstract: Science is our best current approximation of the way things work. You cannot do science unless you believe there is a discernable truth inherent to the arrangement of our tangible world. The problem is, we in our given time never know where exactly the asymptote lies or how far we are from it. My curiosity about the natural world is innate, but fate has variously gifted me with outstanding personal opportunities to indulge that curiosity through the study of viruses. To a woman of the boomer generation, professional paths were not always open-door, and to a certain extent they still aren't. Whether such points should now be viewed as obstacles or stepping stones is a matter of perspective. RNA viruses, and the multiple, seminal mentors who taught me their secrets, have defined my career. Some of their stories are told here as they dovetail with mine. If there is any unity to this, it would be a pursuit of the language of life, or sequence analysis, as taught to us by natural selection. The intent here is ...