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Annual Review of Virology - Volume 1, 2014
Volume 1, 2014
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Forty Years with Emerging Viruses
Vol. 1 (2014), pp. 1–23More LessI was raised in a middle-class family in West Texas and was lucky in my preparation through high school faculty, short government programs arising from the politics of Sputnik, inspiring high school mentors, and university training at a first-rate institution. My educational background led me to apply to medical school. With some financial aid, I managed to graduate and then obtain a first-class internal medicine residency at Parkland Hospital, where I acquired skills in discerning evaluation and treatment of patients with complicated diseases. In spite of a liking for and ability in clinical medicine, I entered the Public Health Service and worked for 5 years at the National Institutes of Health laboratory in Panama; there, I began to see the fascination of ecological impacts on virus transmission in nature and its spillover into human populations. I shifted my interests to these themes and their interaction with viral pathogenesis. At each stage of my career, I picked an institution to work where there were strong leaders and other inspiring scientists. I think the young scientist should choose the best available institution and one that offers a career direction that leads to a life where he or she awakens and cannot wait to arrive at his or her job—regardless of the details of each choice, the outcome will be a satisfied person who will contribute greatly to his or her chosen field.
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Inventing Viruses
Vol. 1 (2014), pp. 25–35More LessIn the nineteenth century, “virus” commonly meant an agent (usually unknown) that caused disease in inoculation experiments. By the 1890s, however, some disease-causing agents were found to pass through filters that retained the common bacteria. Such an agent was called “filterable virus,” the best known being the virus that caused tobacco mosaic disease. By the 1920s there were many examples of filterable viruses, but no clear understanding of their nature. However, by the 1930s, the term “filterable virus” was being abandoned in favor of simply “virus,” meaning an agent other than bacteria. Visualization of viruses by the electron microscope in the late 1930s finally settled their particulate nature. This article describes the ever-changing concept of “virus” and how virologists talked about viruses. These changes reflected their invention and reinvention of the concept of a virus as it was revised in light of new knowledge, new scientific values and interests, and new hegemonic technologies.
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PHIRE and TWiV: Experiences in Bringing Virology to New Audiences
Vol. 1 (2014), pp. 37–53More LessVirology encompasses a broad spectrum of topics touching upon many aspects of our everyday lives. However, appreciation of this impact is too often restricted to those who have specialized training and participate in virology research. The Phage Hunters Integrating Research and Education (PHIRE) program and the This Week in Virology (TWiV) podcast seek to bring virology to new audiences through two different approaches—direct involvement of undergraduates in discovering and genomically characterizing bacteriophages (PHIRE) and clear, accessible, and free discussions among experts of all topics in virology (TWiV). Here we discuss these two high-impact programs, the audiences that they serve, their broader impacts, and their future potential.
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Viruses and the Microbiota
Vol. 1 (2014), pp. 55–69More LessEvery surface of the human body is colonized by a diverse microbial community called the microbiota, yet the impact of this community on viruses is unclear. Recent research has advanced our understanding of how microbiota influence viral infection. Microbiota inhibit infection by some viruses and promote infection by others. These effects can occur through direct and/or indirect effects on the host and/or the virus. This review examines the known effects and mechanisms by which microbiota influence mammalian virus infections. Furthermore, we suggest strategies for future research on how microbiota impact viruses. Overall, microbiota may influence a wide array of viruses through diverse mechanisms, making the study of virus-microbiota interactions a fertile area for future investigation.
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Role of the Vector in Arbovirus Transmission
Vol. 1 (2014), pp. 71–88More LessMany arboviral diseases are uncontrolled, and the viruses that cause them are globally emerging or reemerging pathogens that produce significant disease throughout the world. The increased spread and prevalence of disease are occurring during a period of substantial scientific growth in the vector-borne disease research community. This growth has been supported by advances in genomics and proteomics, and by the ability to genetically alter disease vectors. For the first time, researchers are elucidating the molecular details of vector host-seeking behavior, the susceptibility of disease vectors to arboviruses, the immunological control of infection in disease vectors, and the determinants that facilitate transmission of arboviruses from a vector to a host. These discoveries are facilitating the development of novel strategies to combat arboviral disease, including the release of transgenic mosquitoes harboring dominant lethal genes, the introduction of arbovirus-blocking microbes into mosquito populations, and the development of acquisition- and transmission-blocking therapeutics. Understanding the role of the vector in arbovirus transmission has provided critical practical and theoretical tools to control arboviral disease.
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Balance and Stealth: The Role of Noncoding RNAs in the Regulation of Virus Gene Expression
Vol. 1 (2014), pp. 89–109More LessIn the past two decades, our knowledge of gene regulation has been greatly expanded by the discovery of microRNAs (miRNAs). miRNAs are small (19–24 nt) noncoding RNAs (ncRNAs) found in metazoans, plants, and some viruses. They have been shown to regulate many cellular processes, including differentiation, maintenance of homeostasis, apoptosis, and the immune response. At present, there are over 300 known viral miRNAs encoded by diverse virus families. One well-characterized function of some viral miRNAs is the regulation of viral transcripts. Host miRNAs can also regulate viral gene expression. We propose that viruses take advantage of both host and viral ncRNA regulation to balance replication and infectious state (for example, latent versus lytic infection). As miRNA regulation can be reversed upon certain cellular stresses, we hypothesize that ncRNAs can serve viruses as barometers for cellular stress.
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Thinking Outside the Triangle: Replication Fidelity of the Largest RNA Viruses
Vol. 1 (2014), pp. 111–132More LessWhen judged by ubiquity, adaptation, and emergence of new diseases, RNA viruses are arguably the most successful biological organisms. This success has been attributed to a defect of sorts: high mutation rates (low fidelity) resulting in mutant swarms that allow rapid selection for fitness in new environments. Studies of viruses with small RNA genomes have identified fidelity determinants in viral RNA-dependent RNA polymerases and have shown that RNA viruses likely replicate within a limited fidelity range to maintain fitness. In this review we compare the fidelity of small RNA viruses with that of the largest RNA viruses, the coronaviruses. Coronaviruses encode the first known viral RNA proofreading exoribonuclease, a function that likely allowed expansion of the coronavirus genome and that dramatically increases replication fidelity and the range of tolerated variation. We propose models for regulation of coronavirus fidelity and discuss the implications of altered fidelity for RNA virus replication, pathogenesis, and evolution.
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The Placenta as a Barrier to Viral Infections
Vol. 1 (2014), pp. 133–146More LessThroughout pregnancy, the placenta acts as a physical and immunological barrier against the hematogenous transmission of viruses from mother to fetus. Despite this, very little is known regarding the specific mechanisms by which the placenta shields the developing fetus from viral infections or about the strategies utilized by select viruses to bypass and/or weaken the placental barrier. In this review, we summarize studies regarding virus-host interactions at the placental interface and explore key areas for future investigation. We focus our review on placental trophoblasts, which form the barrier between maternal and fetal circulations and thus govern the cross talk between the maternal and fetal microenvironments.
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Cytoplasmic RNA Granules and Viral Infection
Vol. 1 (2014), pp. 147–170More LessRNA granules are dynamic cellular structures essential for proper gene expression and homeostasis. The two principal types of cytoplasmic RNA granules are stress granules, which contain stalled translation initiation complexes, and processing bodies (P bodies), which concentrate factors involved in mRNA degradation. RNA granules are associated with gene silencing of transcripts; thus, viruses repress RNA granule functions to favor replication. This article discusses the breadth of viral interactions with cytoplasmic RNA granules, focusing on mechanisms that modulate the functions of RNA granules and that typically promote viral replication. Currently, mechanisms for virus manipulation of RNA granules can be loosely grouped into three nonexclusive categories: (a) cleavage of key RNA granule factors, (b) regulation of PKR activation, and (c) co-opting of RNA granule factors for new roles in viral replication. Viral modulation of RNA granules supports productive infection by inhibiting their gene-silencing functions and counteracting their role in linking stress sensing with innate immune activation.
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Mechanisms of Virus Membrane Fusion Proteins
Vol. 1 (2014), pp. 171–189More LessEnveloped viruses infect host cells by a membrane fusion reaction that takes place at the cell surface or in intracellular compartments following virus uptake. Fusion is mediated by the membrane interactions and conformational changes of specialized virus envelope proteins termed membrane fusion proteins. This article discusses the structures and refolding reactions of specific fusion proteins and the methods for their study and highlights outstanding questions in the field.
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Oncolytic Poxviruses
Vol. 1 (2014), pp. 191–214More LessCurrent standard treatments of cancer can prolong survival of many cancer patients but usually do not effectively cure the disease. Oncolytic virotherapy is an emerging therapeutic for the treatment of cancer that exploits replication-competent viruses to selectively infect and destroy cancerous cells while sparing normal cells and tissues. Clinical and/or preclinical studies on oncolytic viruses have revealed that the candidate viruses being tested in trials are remarkably safe and offer potential for treating many classes of currently incurable cancers. Among these candidates are vaccinia and myxoma viruses, which belong to the family Poxviridae and possess promising oncolytic features. This article describes poxviruses that are being developed for oncolytic virotherapy and summarizes the outcomes of both clinical and preclinical studies. Additionally, studies demonstrating superior efficacy when poxvirus oncolytic virotherapy is combined with conventional therapies are described.
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Herpesvirus Genome Integration into Telomeric Repeats of Host Cell Chromosomes
Vol. 1 (2014), pp. 215–235More LessIt is well known that numerous viruses integrate their genetic material into host cell chromosomes. Human herpesvirus 6 (HHV-6) and oncogenic Marek's disease virus (MDV) have been shown to integrate their genomes into host telomeres of latently infected cells. This is unusual for herpesviruses as most maintain their genomes as circular episomes during the quiescent stage of infection. The genomic DNA of HHV-6, MDV, and several other herpesviruses harbors telomeric repeats (TMRs) that are identical to host telomere sequences (TTAGGG). At least in the case of MDV, viral TMRs facilitate integration into host telomeres. Integration of HHV-6 occurs not only in lymphocytes but also in the germline of some individuals, allowing vertical virus transmission. Although the molecular mechanism of telomere integration is poorly understood, the presence of TMRs in a number of herpesviruses suggests it is their default program for genome maintenance during latency and also allows efficient reactivation.
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Viral Manipulation of Plant Host Membranes
Vol. 1 (2014), pp. 237–259More LessPlant viruses, like animal viruses, induce the formation of novel intracellular membranous structures that provide an optimum environment for coordinating diverse viral processes such as viral RNA synthesis and virus egress. Membrane reshaping is accomplished by the expression of specific membrane-associated viral proteins that interact with host proteins involved in membrane trafficking processes. Plant virus–induced membranous structures are motile, and this intracellular motility is required for the transport of viral RNA from sites of synthesis to plasmodesmata, which are used to move viral RNA from cell to cell. Cellular movement of these virus-induced bodies requires myosin motor activity and is dependent on the secretory pathway. The coupling of membrane-associated replication complexes with virus intra- and intercellular trafficking may explain why viral infection of neighboring cells is established rapidly and efficiently.
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IFITM-Family Proteins: The Cell's First Line of Antiviral Defense
Vol. 1 (2014), pp. 261–283More LessAnimal cells use a wide variety of mechanisms to slow or prevent replication of viruses. These mechanisms are usually mediated by antiviral proteins whose expression and activities can be constitutive but are frequently amplified by interferon induction. Among these interferon-stimulated proteins, members of the IFITM (interferon-induced transmembrane) family are unique because they prevent infection before a virus can traverse the lipid bilayer of the cell. At least three human IFITM proteins—IFITM1, IFITM2, and IFITM3—have antiviral activities. These activities limit infection in cultured cells by many viruses, including dengue virus, Ebola virus, influenza A virus, severe acute respiratory syndrome coronavirus, and West Nile virus. Murine Ifitm3 controls influenza A virus infection in vivo, and polymorphisms in human IFITM3 correlate with the severity of both seasonal and highly pathogenic avian influenza virus. Here we review the discovery and characterization of the IFITM proteins, describe the spectrum of their antiviral activities, and discuss potential mechanisms underlying these effects.
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Glycan Engagement by Viruses: Receptor Switches and Specificity
Vol. 1 (2014), pp. 285–306More LessA large number of viruses, including many human pathogens, bind cell-surface glycans during the initial steps of infection. Viral glycan receptors such as glycosaminoglycans and sialic acid–containing carbohydrates are often negatively charged, but neutral glycans such as histo–blood group antigens can also function as receptors. The engagement of glycans facilitates attachment and entry and, consequently, is often a key determinant of the host range, tissue tropism, pathogenicity, and transmissibility of viruses. Here, we review current knowledge about virus-glycan interactions using representative crystal structures of viral attachment proteins in complex with glycans. We illuminate the determinants of specificity utilized by different glycan-binding viruses and explore the potential of these interactions for switching receptor specificities within or even between glycan classes. A detailed understanding of these parameters is important for the prediction of binding sites where structural information is not available, and is invaluable for the development of antiviral therapeutics.
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Remarkable Mechanisms in Microbes to Resist Phage Infections
Vol. 1 (2014), pp. 307–331More LessBacteriophages (phages) specifically infect bacteria and are the most abundant biological entities on Earth. The constant exposure to phage infection imposes a strong selective pressure on bacteria to develop viral resistance strategies that promote prokaryotic survival. Thus, this parasite-host relationship results in an evolutionary arms race of adaptation and counteradaptation between the interacting partners. The evolutionary outcome is a spectrum of remarkable strategies used by the bacteria and phages as they attempt to coexist. These approaches include adsorption inhibition, injection blocking, abortive infection, toxin-antitoxin, and CRISPR-Cas systems. In this review, we highlight the diverse and complementary antiphage systems in bacteria, as well as the evasion mechanisms used by phages to escape these resistance strategies.
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Polydnaviruses: Nature's Genetic Engineers
Vol. 1 (2014), pp. 333–354More LessVirus-host associations are usually viewed as parasitic, but several studies in recent years have reported examples of viruses that benefit host organisms. The Polydnaviridae are of particular interest because these viruses are all obligate mutualists of insects called parasitoid wasps. Parasitoids develop during their immature stages by feeding inside the body of other insects, which serve as their hosts. Polydnaviruses are vertically transmitted as proviruses through the germ line of wasps but also function as gene delivery vectors that wasps rely upon to genetically manipulate the hosts they parasitize. Here we review the evolutionary origin of polydnaviruses, the organization and function of their genomes, and some of their roles in parasitism.
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Human Cytomegalovirus: Coordinating Cellular Stress, Signaling, and Metabolic Pathways
Vol. 1 (2014), pp. 355–374More LessViruses face a multitude of challenges when they infect a host cell. Cells have evolved innate defenses to protect against pathogens, and an infecting virus may induce a stress response that antagonizes viral replication. Further, the metabolic, oxidative, and cell cycle state may not be conducive to the viral infection. But viruses are fabulous manipulators, inducing host cells to use their own characteristic mechanisms and pathways to provide what the virus needs. This article centers on the manipulation of host cell metabolism by human cytomegalovirus (HCMV). We review the features of the metabolic program instituted by the virus, discuss the mechanisms underlying these dramatic metabolic changes, and consider how the altered program creates a synthetic milieu that favors efficient HCMV replication and spread.
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