Finding, Conducting, and Nurturing Science: A Virologist's Memoir Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Anna Marie (Ann) Skalka
My laboratory investigations have been driven by an abiding interest in understanding the consequences of genetic rearrangement in evolution and disease, and in using viruses to elucidate fundamental mechanisms in biology. Starting with bacteriophages and moving to the retroviruses, my use of the tools of genetics, molecular biology, biochemistry, and biophysics has spanned more than half a century—from the time when DNA structure was just discovered to the present day of big data and epigenetics. Both riding and contributing to the successive waves of technology, my laboratory has elucidated fundamental mechanisms in DNA replication, repair, and recombination. We have made substantial contributions in the area of retroviral oncogenesis, delineated mechanisms that control retroviral gene expression, and elucidated critical details of the structure and function of the retroviral enzymes—reverse transcriptase, protease, and integrase—and have had the satisfaction of knowing that the fundamental knowledge gained from these studies contributed important groundwork for the eventual development of antiviral drugs to treat AIDS. While pursuing laboratory research as a principal investigator, I have also been a science administrator—moving from laboratory head to department chair and, finally, to institute director. In addition, I have undertaken a number of community service, science-related “extracurricular” activities during this time. Filling all of these roles, while being a wife and mother, has required family love and support, creative management, and, above all, personal flexibility—with not too much long-term planning. I hope that this description of my journey, with various roles, obstacles, and successes, will be both interesting and informative, especially to young female scientists.
The Discovery, Mechanisms, and Evolutionary Impact of Anti-CRISPRs Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Adair L. Borges, Alan R. Davidson, Joseph Bondy-Denomy
Bacteria and archaea use CRISPR-Cas adaptive immune systems to defend themselves from infection by bacteriophages (phages). These RNA-guided nucleases are powerful weapons in the fight against foreign DNA, such as phages and plasmids, as well as a revolutionary gene editing tool. Phages are not passive bystanders in their interactions with CRISPR-Cas systems, however; recent discoveries have described phage genes that inhibit CRISPR-Cas function. More than 20 protein families, previously of unknown function, have been ascribed anti-CRISPR function. Here, we discuss how these CRISPR-Cas inhibitors were discovered and their modes of action were elucidated. We also consider the potential impact of anti-CRISPRs on bacterial and phage evolution. Finally, we speculate about the future of this field.
Giant Viruses of Amoebae: A Journey Through Innovative Research and Paradigm Changes Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Philippe Colson, Bernard La Scola, Didier Raoult
Giant viruses of amoebae were discovered serendipitously in 2003; they are visible via optical microscopy, making them bona fide microbes. Their lifestyle, structure, and genomes break the mold of classical viruses. Giant viruses of amoebae are complex microorganisms. Their genomes harbor between 444 and 2,544 genes, including many that are unique to viruses, and encode translation components; their virions contain >100 proteins as well as mRNAs. Mimiviruses have a specific mobilome, including virophages, provirophages, and transpovirons, and can resist virophages through a system known as MIMIVIRE (mimivirus virophage resistance element). Giant viruses of amoebae bring upheaval to the definition of viruses and tend to separate the current virosphere into two categories: very simple viruses and viruses with complexity similar to that of other microbes. This new paradigm is propitious for enhanced detection and characterization of giant viruses of amoebae, and a particular focus on their role in humans is warranted.
The Distribution, Evolution, and Roles of Gene Transfer Agents in Prokaryotic Genetic Exchange Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Andrew S. Lang, Alexander B. Westbye, J. Thomas Beatty
Diverse prokaryotes produce gene transfer agents (GTAs), which are bacteriophage-like particles that exclusively package pieces of the producing cell's genome and transfer them to other cells. There are clear evolutionary connections between GTAs and phages, but GTAs have properties that lead us to suggest they are more than simply defective phages and instead provide a selective advantage for the producing organisms. The five types of currently known GTAs are genetically distinct, indicating multiple instances of convergent evolution. GTA production can be regulated by the producing organism and coordinated to coincide with development of the capability to receive DNA from GTAs. Recent discoveries of the genetic basis of GTA production in the bacterium Rhodobacter capsulatus and characterization of novel phages that possess homologs of this GTA's structural and regulatory genes have provided important new connections among these elements and highlight the tangled evolutionary relationships within the phageome.
Constraints, Drivers, and Implications of Influenza A Virus Reassortment Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Anice C. Lowen
Influenza A viruses are constantly changing. This change accounts for seasonal epidemics, infrequent pandemics, and zoonotic outbreaks. A major mechanism underlying the genetic diversification of influenza A virus is reassortment of intact gene segments between coinfecting viruses. This exchange is possible because of the segmented nature of the viral genome. Here, I first consider the constraints and drivers acting on influenza A virus reassortment, including the likelihood of coinfection at the host and cellular levels, mixing and assembly of heterologous gene segments within coinfected cells, and the fitness associated with reassortant genotypes. I then discuss the implications of reassortment for influenza A virus evolution, including its classically recognized role in the emergence of genetically “shifted” pandemic strains as well as its potential role as a catalyst of genetic drift.
Symbiosis: Viruses as Intimate Partners Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Marilyn J. Roossinck, Edelio R. Bazán
Viruses must establish an intimate relationship with their hosts and vectors in order to infect, replicate, and disseminate; hence, viruses can be considered as symbionts with their hosts. Symbiotic relationships encompass different lifestyles, including antagonistic (or pathogenic, the most well-studied lifestyle for viruses), commensal (probably the most common lifestyle), and mutualistic (important beneficial partners). Symbiotic relationships can shape the evolution of the partners in a holobiont, and placing viruses in this context provides an important framework for understanding virus-host relationships and virus ecology. Although antagonistic relationships are thought to lead to coevolution, this is not always clear in virus-host interactions, and impacts on evolution may be complex. Commensalism implies a hitchhiking role for viruses—selfish elements just along for the ride. Mutualistic relationships have been described in detail in the past decade, and they reveal how important viruses are in considering host ecology. Ultimately, symbiosis can lead to symbiogenesis, or speciation through fusion, and the presence of large amounts of viral sequence in the genomes of everything from bacteria to humans, including some important functional genes, illustrates the significance of viral symbiogenesis in the evolution of all life on Earth.
New World Arenavirus Biology Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Nicolás Sarute, Susan R. Ross
Hemorrhagic fevers caused by viruses were identified in the late 1950s in South America. These viruses have existed in their hosts, the New World rodents, for millions of years. Their emergence as infectious agents in humans coincided with changes in the environment and farming practices that caused explosions in their host rodent populations. Zoonosis into humans likely occurs because the pathogenic New World arenaviruses use human transferrin receptor 1 to enter cells. The mortality rate after infection with these viruses is high, but the mechanism by which disease is induced is still not clear. Possibilities include direct effects of cellular infection or the induction of high levels of cytokines by infected sentinel cells of the immune system, leading to endothelia and thrombocyte dysfunction and neurological disease. Here we provide a review of the ecology and molecular and cellular biology of New World arenaviruses, as well as a discussion of the current animal models of infection. The development of animal models, coupled with an improved understanding of the infection pathway and host response, should lead to the discovery of new drugs for treating infections.
Viruses with Circular Single-Stranded DNA Genomes Are Everywhere! Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 L.M. Shulman, I. Davidson
Circular single-stranded DNA viruses infect archaea, bacteria, and eukaryotic organisms. The relatively recent emergence of single-stranded DNA viruses, such as chicken anemia virus (CAV) and porcine circovirus 2 (PCV2), as serious pathogens of eukaryotes is due more to growing awareness than to the appearance of new pathogens or alteration of existing pathogens. In the case of the ubiquitous human circular single-stranded DNA virus family Anelloviridae, there is still no convincing direct causal relation to any specific disease. However, infections may play a role in autoimmunity by changing the homeostatic balance of proinflammatory cytokines and the human immune system, indirectly affecting the severity of diseases caused by other pathogens. Infections with CAV (family Anelloviridae, genus Gyrovirus) and PCV2 (family Circoviridae, genus Circovirus) are presented here because they are immunosuppressive and affect health in domesticated animals. CAV shares genomic organization, genomic orientation, and common features of major proteins with human anelloviruses, and PCV2 DNA may be present in human food and vaccines.
The Bridges and Blockades to Evolutionary Convergence on the Road to Predicting Chikungunya Virus Evolution Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Marco Vignuzzi, Stephen Higgs
Chikungunya virus, first isolated in the 1950s, has since reemerged to cause several epidemics and millions of infections throughout the world. What was once blurred and confused with dengue virus in both diagnosis and name has since become one of the best-characterized arboviral diseases. In this review, we cover the history of this virus, its evolution into distinct genotypes and lineages, and, most notably, the convergent evolution observed in recent years. We highlight research that reveals to what extent convergent evolution, and its inherent predictability, may occur and what genetic or environmental factors may hinder it.
Viruses in Soil Ecosystems: An Unknown Quantity Within an Unexplored Territory Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Kurt E. Williamson, Jeffry J. Fuhrmann, K. Eric Wommack, Mark Radosevich
Viral abundance in soils can range from below detection limits in hot deserts to over 1 billion per gram in wetlands. Abundance appears to be strongly influenced by water availability and temperature, but a lack of informational standards creates difficulties for cross-study analysis. Soil viral diversity is severely underestimated and undersampled, although current measures of viral richness are higher for soils than for aquatic ecosystems. Both morphometric and metagenomic analyses have raised questions about the prevalence of nontailed, ssDNA viruses in soils. Soil is complex and critically important to terrestrial biodiversity and human civilization, but impacts of viral activities on soil ecosystem services are poorly understood. While information from aquatic systems and medical microbiology suggests the potential for viral influences on nutrient cycles, food web interactions, gene transfer, and other key processes in soils, very few empirical data are available. To understand the soil virome, much work remains.
Enzymes and Enzyme Activity Encoded by Nonenveloped Viruses Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Kimi Azad, Manidipa Banerjee, John E. Johnson
Viruses are obligate intracellular parasites that rely on host cell machineries for their replication and survival. Although viruses tend to make optimal use of the host cell protein repertoire, they need to encode essential enzymatic or effector functions that may not be available or accessible in the host cellular milieu. The enzymes encoded by nonenveloped viruses—a group of viruses that lack any lipid coating or envelope—play vital roles in all the stages of the viral life cycle. This review summarizes the structural, biochemical, and mechanistic information available for several classes of enzymes and autocatalytic activity encoded by nonenveloped viruses. Advances in research and development of antiviral inhibitors targeting specific viral enzymes are also highlighted.
Making Sense of Multifunctional Proteins: Human Immunodeficiency Virus Type 1 Accessory and Regulatory Proteins and Connections to Transcription Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Tyler B. Faust, Jennifer M. Binning, John D. Gross, Alan D. Frankel
Viruses are completely dependent upon cellular machinery to support replication and have therefore developed strategies to co-opt cellular processes to optimize infection and counter host immune defenses. Many viruses, including human immunodeficiency virus type 1 (HIV-1), encode a relatively small number of genes. Viruses with limited genetic content often encode multifunctional proteins that function at multiple stages of the viral replication cycle. In this review, we discuss the functions of HIV-1 regulatory (Tat and Rev) and accessory (Vif, Vpr, Vpu, and Nef) proteins. Each of these proteins has a highly conserved primary activity; however, numerous additional activities have been attributed to these viral proteins. We explore the possibility that HIV-1 proteins leverage their multifunctional nature to alter host transcriptional networks to elicit a diverse set of cellular responses. Although these transcriptional effects appear to benefit the virus, it is not yet clear whether they are strongly selected for during viral evolution or are a ripple effect from the primary function. As our detailed knowledge of these viral proteins improves, we will undoubtedly uncover how the multifunctional nature of these HIV-1 regulatory and accessory proteins, and in particular their transcriptional functions, work to drive viral pathogenesis.
The Molecular Basis for Human Immunodeficiency Virus Latency Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Uri Mbonye, Jonathan Karn
Although potent combination antiretroviral therapy can effectively block viral replication in the host, human immunodeficiency virus (HIV) persists due to the existence of latent but replication-competent proviruses residing primarily in a very small population of resting memory CD4+ T cells. Viral latency is established when the expression of the autoregulatory viral trans-activating factor Tat is reduced to subthreshold levels. The absence of Tat reduces HIV transcription and protein production to levels that make the host cell invisible to the immune system and refractory to antiretroviral treatment. Key host cell mechanisms that drive HIV into latency are sequestration of transcription initiation factors, establishment of epigenetic barriers inactivating the proviral promoter, and blockage of the assembly of the host elongation factor P-TEFb. This comprehensive understanding of the molecular control of HIV transcription is leading to the development of optimized combinatorial reactivation and immune surveillance strategies designed to purge the latent viral reservoir.
Electron Cryomicroscopy of Viruses at Near-Atomic Resolutions Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Jason T. Kaelber, Corey F. Hryc, Wah Chiu
Recently, dozens of virus structures have been solved to resolutions between 2.5 and 5.0 Å by means of electron cryomicroscopy. With these structures we are now firmly within the “atomic age” of electron cryomicroscopy, as these studies can reveal atomic details of protein and nucleic acid topology and interactions between specific residues. This improvement in resolution has been the result of direct electron detectors and image processing advances. Although enforcing symmetry facilitates reaching near-atomic resolution with fewer particle images, it unfortunately obscures some biologically interesting components of a virus. New approaches on relaxing symmetry and exploring structure dynamics and heterogeneity of viral assemblies have revealed important insights into genome packaging, virion assembly, cell entry, and other stages of the viral life cycle. In the future, novel methods will be required to reveal yet-unknown structural conformations of viruses, relevant to their biological activities. Ultimately, these results hold the promise of answering many unresolved questions linking structural diversity of viruses to their biological functions.
A Consensus View of ESCRT-Mediated Human Immunodeficiency Virus Type 1 Abscission Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 J. Lippincott-Schwartz, E.O. Freed, S.B. van Engelenburg
The strong dependence of retroviruses, such as human immunodeficiency virus type 1 (HIV-1), on host cell factors is no more apparent than when the endosomal sorting complex required for transport (ESCRT) machinery is purposely disengaged. The resulting potent inhibition of retrovirus release underscores the importance of understanding fundamental structure-function relationships at the ESCRT–HIV-1 interface. Recent studies utilizing advanced imaging technologies have helped clarify these relationships, overcoming hurdles to provide a range of potential models for ESCRT-mediated virus abscission. Here, we discuss these models in the context of prior work detailing ESCRT machinery and the HIV-1 release process. To provide a template for further refinement, we propose a new working model for ESCRT-mediated HIV-1 release that reconciles disparate and seemingly conflicting studies.
Astrovirus Biology and Pathogenesis Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Valerie Cortez, Victoria A. Meliopoulos, Erik A. Karlsson, Virginia Hargest, Cydney Johnson, Stacey Schultz-Cherry
Astroviruses are nonenveloped, positive-sense single-stranded RNA viruses that cause gastrointestinal illness. Although a leading cause of pediatric diarrhea, human astroviruses are among the least characterized enteric RNA viruses. However, by using in vitro methods and animal models to characterize virus-host interactions, researchers have discovered several important properties of astroviruses, including the ability of the astrovirus capsid to act as an enterotoxin, disrupting the gut epithelial barrier. Improved animal models are needed to study this phenomenon, along with the pathogenesis of astroviruses, particularly in those strains that can cause extraintestinal disease. Much like for other enteric viruses, the current dogma states that astroviruses infect in a species-specific manner; however, this assumption is being challenged by growing evidence that these viruses have potential to cross species barriers. This review summarizes these remarkable facets of astrovirus biology, highlighting critical steps toward increasing our understanding of this unique enteric pathogen.
Progressive Multifocal Leukoencephalopathy: Endemic Viruses and Lethal Brain Disease Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Sheila A. Haley, Walter J. Atwood
In 1971, the first human polyomavirus was isolated from the brain of a patient who died from a rapidly progressing demyelinating disease known as progressive multifocal leukoencephalopathy. The virus was named JC virus after the initials of the patient. In that same year a second human polyomavirus was discovered in the urine of a kidney transplant patient and named BK virus. In the intervening years it became clear that both viruses were widespread in the human population but only rarely caused disease. The past decade has witnessed the discovery of eleven new human polyomaviruses, two of which cause unusual and rare cancers. We present an overview of the history of these viruses and the evolution of JC polyomavirus–induced progressive multifocal leukoencephalopathy over three different epochs. We review what is currently known about JC polyomavirus, what is suspected, and what remains to be done to understand the biology of how this mostly harmless endemic virus gives rise to lethal disease.
Defensins in Viral Infection and Pathogenesis Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Mayumi K. Holly, Karina Diaz, Jason G. Smith
α, β, and θ defensins are effectors of the innate immune system with potent antibacterial, antiviral, and antifungal activity. Defensins have direct antiviral activity in cell culture, with varied mechanisms for individual viruses, although some common themes have emerged. In addition, defensins have potent immunomodulatory activity that can alter innate and adaptive immune responses to viral infection. In some cases, there is evidence for paradoxical escape from defensin neutralization or enhancement of viral infection. The direct and indirect activities of defensins have led to their development as therapeutics and vaccine components. The major area of investigation that continues to lag is the connection between the effects of defensins in cell culture models and viral pathogenesis in vivo. Model systems to study defensin biology, including more physiologic models designed to bridge this gap, are also discussed.
Humanized Mouse Models for Human Immunodeficiency Virus Infection Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Matthew D. Marsden, Jerome A. Zack
Human immunodeficiency virus (HIV) remains a significant source of morbidity and mortality worldwide. No effective vaccine is available to prevent HIV transmission, and although antiretroviral therapy can prevent disease progression, it does not cure HIV infection. Substantial effort is therefore currently directed toward basic research on HIV pathogenesis and persistence and developing methods to stop the spread of the HIV epidemic and cure those individuals already infected with HIV. Humanized mice are versatile tools for the study of HIV and its interaction with the human immune system. These models generally consist of immunodeficient mice transplanted with human cells or reconstituted with a near-complete human immune system. Here, we describe the major humanized mouse models currently in use, and some recent advances that have been made in HIV research/therapeutics using these models.
Immunopathology of Chikungunya Virus Infection: Lessons Learned from Patients and Animal Models Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Lisa F.P. Ng
Chikungunya virus (CHIKV) is an arthropod-borne alphavirus that causes acute and chronic arthritis. The virus reemerged in the Indian Ocean islands in 2005–2006 and is responsible for outbreaks in the Caribbean islands and the Americas since late 2013. Despite the wealth of research over the past 10 years, there are no commercially available antiviral drugs or vaccines. Treatment usually involves analgesics, anti-inflammatory drugs, and supportive care. Most studies have been focused on understanding the pathogenesis of CHIKV infection through clinical observation and with animal models. In this review, the clinical manifestations of CHIKV that define the disease and the use of relevant animal models, from mice to nonhuman primates, are discussed. Understanding key cellular factors in CHIKV infection and the interplay with the immune system will aid in the development of preventive and therapeutic approaches to combat this painful viral disease in humans.
Cassava Mosaic and Brown Streak Diseases: Current Perspectives and Beyond Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Chrissie Rey, Hervé Vanderschuren
Cassava is the fourth largest source of calories in the world but is subject to economically important yield losses due to viral diseases, including cassava brown streak disease and cassava mosaic disease. Cassava mosaic disease occurs in sub-Saharan Africa and the Asian subcontinent and is associated with nine begomovirus species, whereas cassava brown streak disease has to date been reported only in sub-Saharan Africa and is caused by two distinct ipomovirus species. We present an overview of key milestones and their significance in the understanding and characterization of these two major diseases as well as their associated viruses and whitefly vector. New biotechnologies offer a wide range of opportunities to reduce virus-associated yield losses in cassava for farmers and can additionally enable the exploitation of this valuable crop for industrial purposes. This review explores established and new technologies for genetic manipulation to achieve desired traits such as virus resistance.
Phage Tail–Like Bacteriocins Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Dean Scholl
Many dsDNA bacterial viruses (bacteriophages/phages) have long tail structures that serve as organelles for DNA delivery to host targets. These structures, particularly those of Myoviridae and Siphoviridae phages, have an evolutionary relationship with other cellular biological entities that share the common function of penetrating the bacterial envelope. Among these are type VI secretion systems, insecticidal protein complexes, and bacteriocins. Phage tail–like bacteriocins (PTLBs) are widespread in bacteria, comprising different types that likely evolved independently. They can be divided into two major classes: the R-type PTLBs, which are related to contractile Myoviridae phage tails, and the F-type PTLBs, which are related to noncontractile Siphoviridae phage tails. This review provides an overview of the history, biology, and diversity of these entities and also covers recent efforts to utilize these potent bactericidal agents as human therapeutics against bacterial disease.
Fate-Regulating Circuits in Viruses: From Discovery to New Therapy Targets Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Anand Pai, Leor S. Weinberger
Current antivirals effectively target diverse viruses at various stages of their life cycles. Nevertheless, curative therapy has remained elusive for important pathogens, such as human immunodeficiency virus type 1 (HIV-1) and herpesviruses, in large part due to viral latency and the evolution of resistance to existing therapies. Here, we review the discovery of viral master circuits: virus-encoded autoregulatory gene networks that autonomously control viral expression programs (i.e., between active, latent, and abortive fates). These circuits offer the opportunity for a new class of antivirals that could lead to intrinsic combination-antiviral therapies within a single molecule—evolutionary escape from such circuit-disrupting antivirals would require simultaneous evolution of both the viral cis regulatory element (e.g., the DNA-binding site) and the trans element (e.g., the transcription factor) in order for the virus to recapitulate a circuit that would not be disrupted. We review the architectures of these fate-regulating master circuits in HIV-1 and the human herpesvirus cytomegalovirus along with potential circuit-disruption strategies that may ultimately enable escape-resistant antiviral therapies.
Engineered Expression of Broadly Neutralizing Antibodies Against Human Immunodeficiency Virus Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Maham Ahmad, Osama M. Ahmed, Bruce Schnepp, Philip R. Johnson
This review discusses recent progress made in developing a vaccine and novel treatments for human immunodeficiency virus (HIV). It highlights the shortcomings of the RV144 vaccination trial [ALVAC-HIV (vCP1521) and AIDSVAX B/E] and the current standard of care and proposes that engineered expression of broadly neutralizing antibodies (bNAbs) against HIV-1 could overcome these shortcomings. Current developments in three major lines of research on HIV prevention and treatment using bNAbs are reviewed: firstly, the use of sequential immunogens to activate B cells to express bNAbs; secondly, the delivery of novel and extremely potent bNAbs through passive administration; and finally, the use of gene transfer using adeno-associated viral vectors to deliver bNAbs.
Overcoming the Host Immune Response to Adeno-Associated Virus Gene Delivery Vectors: The Race Between Clearance, Tolerance, Neutralization, and Escape Annu. Rev. Virol. (IF 4.143) Pub Date : 2017-09-29 Federico Mingozzi, Katherine A. High
Immune responses in gene therapy with adeno-associated virus (AAV) vectors have been the object of almost two decades of study. Although preclinical models helped to define and predict certain aspects of interactions between the vector and the host immune system, most of our current knowledge has come from clinical trials. These studies have allowed development of effective interventions for modulating immunotoxicities associated with vector administration, resulting in therapeutic advances. However, the road to full understanding and effective modulation of immune responses in gene therapy is still long; the determinants of the balance between tolerance and immunogenicity in AAV vector–mediated gene transfer are not fully understood, and effective solutions for overcoming preexisting neutralizing antibodies are still lacking. However, despite these challenges, the goal of reliably delivering effective gene-based treatments is now in sight.
Rotavirus Strategies Against the Innate Antiviral System Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Susana López, Liliana Sánchez-Tacuba, Joaquin Moreno, Carlos F. Arias
“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 host cells has allowed us to learn about the virus–host coevolution that prevents the damaging effects of the innate immune response.
Bugs Are Not to Be Silenced: Small RNA Pathways and Antiviral Responses in Insects Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Vanesa Mongelli, Maria-Carla Saleh
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.
Modeling Viral Spread Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Frederik Graw, Alan S. Perelson
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.
Viruses and the Diversity of Cell Death Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Pranav Danthi
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.
Polyomavirus Persistence Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Michael J. Imperiale, Mengxi Jiang
Mammalian polyomaviruses are characterized by establishing persistent infections in healthy hosts and generally causing clinical disease only in hosts whose immune systems are compromised. Despite the fact that these viruses were discovered decades ago, our knowledge of the mechanisms that govern viral persistence and reactivation is limited. Whereas mouse polyomavirus has been studied in a fair amount of detail, our understanding of the human viruses in particular is mostly inferred from experiments aimed at addressing other questions. In this review, we summarize the state of our current knowledge, draw conclusions when possible, and suggest areas that are in need of further study.
Tombusvirus-Host Interactions: Co-Opted Evolutionarily Conserved Host Factors Take Center Court Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Peter D. Nagy
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.
Transgenic Mouse Models of Tumor Virus Action Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Paul F. Lambert
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.
Single-Cell Studies of Phage λ: Hidden Treasures Under Occam's Rug Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Ido Golding
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.
The Structural Biology of Hepatitis B Virus: Form and Function Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Balasubramanian Venkatakrishnan, Adam Zlotnick
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.
Moving On Out: Transport and Packaging of Influenza Viral RNA into Virions Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Seema S. Lakdawala, Ervin Fodor, Kanta Subbarao
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.
Nuclear Exodus: Herpesviruses Lead the Way Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Janna M. Bigalke, Ekaterina E. Heldwein
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.
More than Meets the Eye: Hidden Structures in the Proteome Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Hal Wasserman, Erica Ollmann Saphire
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.
Epstein-Barr Virus: The Path from Latent to Productive Infection Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Ya-Fang Chiu, Bill Sugden
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.
Human Cytomegalovirus Latency: Approaching the Gordian Knot Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Felicia Goodrum
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.
Unraveling the Mysterious Interactions Between Hepatitis C Virus RNA and Liver-Specific MicroRNA-122 Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Peter Sarnow, Selena M. Sagan
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 from phase II clinical trials in patients treated with miR-122 antisense oligonucleotides.
A Cap-to-Tail Guide to mRNA Translation Strategies in Virus-Infected Cells Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Eric Jan, Ian Mohr, Derek Walsh
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.
Structure, Function, and Evolution of Coronavirus Spike Proteins Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Fang Li
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 functions from other viruses and host cells.
Properties and Functions of the Dengue Virus Capsid Protein Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Laura A. Byk, Andrea V. Gamarnik
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 as Winners in the Game of Life Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Ana Georgina Cobián Güemes, Merry Youle, Vito Adrian Cantú, Ben Felts, James Nulton, Forest Rohwer
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.
Integrins as Herpesvirus Receptors and Mediators of the Host Signalosome Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Gabriella Campadelli-Fiume, Donna Collins-McMillen, Tatiana Gianni, Andrew D. Yurochko
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.
Genomic Analysis of Viral Outbreaks Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Shirlee Wohl, Stephen F. Schaffner, Pardis C. Sabeti
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.
Epidemiology and Management of the 2013–16 West African Ebola Outbreak Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 M.L. Boisen, J.N. Hartnett, A. Goba, M.A. Vandi, D.S. Grant, J.S. Schieffelin, R.F. Garry, L.M. Branco
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.
Climate Change and the Arboviruses: Lessons from the Evolution of the Dengue and Yellow Fever Viruses Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Walter J. Tabachnick
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 cycles and (b) the role of virus genetic and environmental variances in shaping virus phenotypic variance to more fully assess the impact of global climate change.
The Genus Tospovirus: Emerging Bunyaviruses that Threaten Food Security Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 J.E. Oliver, A.E. Whitfield
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 genus members.
Bats as Viral Reservoirs Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 David T.S. Hayman
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 Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Alex S. Hartlage, John M. Cullen, Amit Kapoor
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.
The Discovery of Reverse Transcriptase Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 John M. Coffin, Hung Fan
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.
The Language of Life Annu. Rev. Virol. (IF 4.143) Pub Date : 2016-10-14 Ann C. Palmenberg
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 not a legacy but an example. Science is a beautiful fate.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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