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- Volume 8, 2021
Annual Review of Virology - Volume 8, 2021
Volume 8, 2021
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I Am Here: It Took a Global Village
Vol. 8 (2021), pp. 1–21More LessThe saying “It takes a village to raise a child” has never been truer than in my case. This autobiographical article documents my growing up and working on three different continents and my influencers along the way. Born in a village in Nigeria, West Africa, I spent the first 12 years of life with my grandmother living in a mud house and attending a village primary school. I walked barefoot to school every day, learned to read, and wrote on a chalk slate. At the age of 13, I moved to my second “village,” London, England. In secondary school my love of science began to blossom. I attained a double major in chemistry and human biology from the University of Hertfordshire and a PhD in biophysics from the University of London, with a research project aimed at designing anticancer agents. I was mentored by Terence Jenkins and Stephen Neidle. For my postdoctoral training, I crossed the ocean again, to the United States, my third “village.” In Michael Rossmann's group at Purdue University, my love for viruses was ignited. My independent career in structural virology began at Warwick University, England, working on pathogenic single-stranded DNA packaging viruses. In 2020, I am a full professor at the University of Florida. Most of my research is focused on the adeno-associated viruses, gene delivery vectors. My list of mentors has grown and includes Nick Muzyczka. Here, the mentee has become the mentor, and along the way, we attained a number of firsts in the field of structural virology and contributed to the field at the national and international stages.
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Reflections on a Career in Plant Virology: A Chip Floating on a Stream
Vol. 8 (2021), pp. 23–50More LessAt the time I entered college and for a few years afterward, I had very few concrete goals. Hence, my progress was more a matter of luck than planning and was somewhat analogous to a small wood chip floating down a slow stream, bumping into various objects tossed and turned hither and thither, all the while being surrounded by larger and more appealing chips. I have been extremely lucky to have been associated with numerous helpful and knowledgeable mentors, colleagues, postdocs, students, and coworkers whose advice had major impacts on my life. Therefore, throughout this article, I have attempted to acknowledge central individuals who contributed to my progress in academia and to highlight the positive bumps to my chip on the steam that affected the directions of my career.
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Historical Perspective on the Discovery of the Quasispecies Concept
Vol. 8 (2021), pp. 51–72More LessViral quasispecies are dynamic distributions of nonidentical but closely related mutant and recombinant viral genomes subjected to a continuous process of genetic variation, competition, and selection that may act as a unit of selection. The quasispecies concept owes its theoretical origins to a model for the origin of life as a collection of mutant RNA replicators. Independently, experimental evidence for the quasispecies concept was obtained from sampling of bacteriophage clones, which revealed that the viral populations consisted of many mutant genomes whose frequency varied with time of replication. Similar findings were made in animal and plant RNA viruses. Quasispecies became a theoretical framework to understand viral population dynamics and adaptability. The evidence came at a time when mutations were considered rare events in genetics, a perception that was to change dramatically in subsequent decades. Indeed, viral quasispecies was the conceptual forefront of a remarkable degree of biological diversity, now evident for cell populations and organisms, not only for viruses. Quasispecies dynamics unveiled complexities in the behavior of viral populations,with consequences for disease mechanisms and control strategies. This review addresses the origin of the quasispecies concept, its major implications on both viral evolution and antiviral strategies, and current and future prospects.
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Understanding the Complex Phage-Host Interactions in Biofilm Communities
Vol. 8 (2021), pp. 73–94More LessBacteriophages and bacterial biofilms are widely present in natural environments, a fact that has accelerated the evolution of phages and their bacterial hosts in these particular niches. Phage-host interactions in biofilm communities are rather complex, where phages are not always merely predators but also can establish symbiotic relationships that induce and strengthen biofilms. In this review we provide an overview of the main features affecting phage-biofilm interactions as well as the currently available methods of studying these interactions. In addition, we address the applications of phages for biofilm control in different contexts.
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Bacteriophage-Bacteria Interactions in the Gut: From Invertebrates to Mammals
Vol. 8 (2021), pp. 95–113More LessBacteria and their viruses (bacteriophages or phages) interact antagonistically and beneficially in polymicrobial communities such as the guts of animals. These interactions are multifaceted and are influenced by environmental conditions. In this review, we discuss phage-bacteria interactions as they relate to the complex environment of the gut. Within the mammalian and invertebrate guts, phages and bacteria engage in diverse interactions including genetic coexistence through lysogeny, and phages directly modulate microbiota composition and the immune system with consequences that are becoming recognized as potential drivers of health and disease. With greater depth of understanding of phage-bacteria interactions in the gut and the outcomes, future phage therapies become possible.
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Interaction of Viruses with the Insect Intestine
Vol. 8 (2021), pp. 115–131More LessIn nature, insects face a constant threat of infection by numerous exogeneous viruses, and their intestinal tracts are the predominant ports of entry. Insects can acquire these viruses orally during either blood feeding by hematophagous insects or sap sucking and foliage feeding by insect herbivores. However, the insect intestinal tract forms several physical and immunological barriers to defend against viral invasion, including cell intrinsic antiviral immunity, the peritrophic matrix and the mucin layer, and local symbiotic microorganisms. Whether an infection can be successfully established in the intestinal tract depends on the complex interactions between viruses and those barriers. In this review, we summarize recent progress on virus-intestinal tract interplay in insects, in which various underlying mechanisms derived from nutritional status, dynamics of symbiotic microorganisms, and virus-encoded components play intricate roles in the regulation of virus invasion in the intestinal tract, either directly or indirectly.
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Integrating Viral Metagenomics into an Ecological Framework
Vol. 8 (2021), pp. 133–158More LessViral metagenomics has expanded our knowledge of the ecology of uncultured viruses, within both environmental (e.g., terrestrial and aquatic) and host-associated (e.g., plants and animals, including humans) contexts. Here, we emphasize the implementation of an ecological framework in viral metagenomic studies to address questions in virology rarely considered ecological, which can change our perception of viruses and how they interact with their surroundings. An ecological framework explicitly considers diverse variants of viruses in populations that make up communities of interacting viruses, with ecosystem-level effects. It provides a structure for the study of the diversity, distributions, dynamics, and interactions of viruses with one another, hosts, and the ecosystem, including interactions with abiotic factors. An ecological framework in viral metagenomics stands poised to broadly expand our knowledge in basic and applied virology. We highlight specific fundamental research needs to capitalize on its potential and advance the field.
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Quantitative Temporal Viromics
Vol. 8 (2021), pp. 159–181More LessThe abundance, localization, modifications, and protein-protein interactions of many host cell and virus proteins can change dynamically throughout the course of any viral infection. Studying these changes is critical for a comprehensive understanding of how viruses replicate and cause disease, as well as for the development of antiviral therapeutics and vaccines. Previously, we developed a mass spectrometry–based technique called quantitative temporal viromics (QTV), which employs isobaric tandem mass tags (TMTs) to allow precise comparative quantification of host and virus proteomes through a whole time course of infection. In this review, we discuss the utility and applications of QTV, exemplified by numerous studies that have since used proteomics with a variety of quantitative techniques to study virus infection through time.
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The Social Life of Viruses
Vol. 8 (2021), pp. 183–199More LessDespite their simplicity, viruses exhibit certain types of social interactions. Situations in which a given virus achieves higher fitness in combination with other members of the viral population have been described at the level of transmission, replication, suppression of host immune responses, and host killing, enabling the evolution of viral cooperation. Although cellular coinfection with multiple viral particles is the typical playground for these interactions, cooperation between viruses infecting different cells is also established through cellular and viral-encoded communication systems. In general, the stability of cooperation is compromised by cheater genotypes, as best exemplified by defective interfering particles. As predicted by social evolution theory, cheater invasion can be avoided when cooperators interact preferentially with other cooperators, a situation that is promoted in spatially structured populations. Processes such as transmission bottlenecks, organ compartmentalization, localized spread of infection foci, superinfection exclusion, and even discrete intracellular replication centers promote multilevel spatial structuring in viruses.
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The Ends Dictate the Means: Promoter Switching in Herpesvirus Gene Expression
Vol. 8 (2021), pp. 201–218More LessHerpesvirus gene expression is dynamic and complex, with distinct complements of viral genes expressed at specific times in different infection contexts. These complex patterns of viral gene expression arise in part from the integration of multiple cellular and viral signals that affect the transcription of viral genes. The use of alternative promoters provides an increased level of control, allowing different promoters to direct the transcription of the same gene in response to distinct temporal and contextual cues. While once considered rare, herpesvirus alternative promoter usage was recently found to be far more pervasive and impactful than previously thought. Here we review several examples of promoter switching in herpesviruses and discuss the functional consequences on the transcriptional and post-transcriptional regulation of viral gene expression.
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Virus Structures and Dynamics by Magic-Angle Spinning NMR
Vol. 8 (2021), pp. 219–237More LessTechniques for atomic-resolution structural biology have evolved during the past several decades. Breakthroughs in instrumentation, sample preparation, and data analysis that occurred in the past decade have enabled characterization of viruses with an unprecedented level of detail. Here we review the recent advances in magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy for structural analysis of viruses and viral assemblies. MAS NMR is a powerful method that yields information on 3D structures and dynamics in a broad range of experimental conditions. After a brief introduction, we discuss recent structural and functional studies of several viruses investigated with atomic resolution at various levels of structural organization, from individual domains of a membrane protein reconstituted into lipid bilayers to virus-like particles and intact viruses. We present examples of the unique information revealed by MAS NMR about drug binding, conduction mechanisms, interactions with cellular host factors, and DNA packaging in biologically relevant environments that are inaccessible by other methods.
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Adenosine Deaminases Acting on RNA (ADARs) and Viral Infections
Vol. 8 (2021), pp. 239–264More LessC6 deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA) is catalyzed by a family of enzymes known as ADARs (adenosine deaminases acting on RNA) encoded by three genes in mammals. Alternative promoters and splicing produce two ADAR1 proteins, an interferon-inducible cytoplasmic p150 and a constitutively expressed p110 that like ADAR2 is a nuclear enzyme. ADAR3 lacks deaminase activity. A-to-I editing occurs with both viral and cellular RNAs. Deamination activity is dependent on dsRNA substrate structure and regulatory RNA-binding proteins and ranges from highly site selective with hepatitis D RNA and glutamate receptor precursor messenger RNA (pre-mRNA) to hyperediting of measles virus and polyomavirus transcripts and cellular inverted Alu elements. Because I base-pairs as guanosine instead of A, editing can alter mRNA decoding, pre-mRNA splicing, and microRNA silencing. Editing also alters dsRNA structure, thereby suppressing innate immune responses including interferon production and action.
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Targeted Restriction of Viral Gene Expression and Replication by the ZAP Antiviral System
Vol. 8 (2021), pp. 265–283More LessThe zinc finger antiviral protein (ZAP) restricts the replication of a broad range of RNA and DNA viruses. ZAP directly binds viral RNA, targeting it for degradation and inhibiting its translation. While the full scope of RNA determinants involved in mediating selective ZAP activity is unclear, ZAP binds CpG dinucleotides, dictating at least part of its target specificity. ZAP interacts with many cellular proteins, although only a few have been demonstrated to be essential for its antiviral activity, including the 3′–5′ exoribonuclease exosome complex, TRIM25, and KHNYN. In addition to inhibiting viral gene expression, ZAP also directly and indirectly targets a subset of cellular messenger RNAs to regulate the innate immune response. Overall, ZAP protects a cell from viral infection by restricting viral replication and regulating cellular gene expression. Further understanding of the ZAP antiviral system may allow for novel viral vaccine and anticancer therapy development.
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Bacteriophage ICP1: A Persistent Predator of Vibrio cholerae
Vol. 8 (2021), pp. 285–304More LessBacteriophages or phages—viruses of bacteria—are abundant and considered to be highly diverse. Interestingly, a particular group of lytic Vibrio cholerae–specific phages (vibriophages) of the International Centre for Diarrheal Disease Research, Bangladesh cholera phage 1 (ICP1) lineage show high levels of genome conservation over large spans of time and geography, despite a constant coevolutionary arms race with their host. From a collection of 67 sequenced ICP1 isolates, mostly from clinical samples, we find these phages have mosaic genomes consisting of large, conserved modules disrupted by variable sequences that likely evolve mostly through mobile endonuclease-mediated recombination during coinfection. Several variable regions have been associated with adaptations against antiphage elements in V. cholerae; notably, this includes ICP1’s CRISPR-Cas system. The ongoing association of ICP1 and V. cholerae in cholera-endemic regions makes this system a rich source for discovery of novel defense and counterdefense strategies in bacteria-phage conflicts in nature.
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Advances in Viroid-Host Interactions
Vol. 8 (2021), pp. 305–325More LessViroids are small, single-stranded, circular RNAs infecting plants. Composed of only a few hundred nucleotides and being unable to code for proteins, viroids represent the lowest level of complexity for an infectious agent, even below that of the smallest known viruses. Despite the relatively small size, viroids contain RNA structural elements embracing all the information needed to interact with host factors involved in their infectious cycle, thus providing models for studying structure-function relationships of RNA. Viroids are specifically targeted to nuclei (family Pospiviroidae) or chloroplasts (family Avsunviroidae), where replication based on rolling-circle mechanisms takes place. They move locally and systemically through plasmodesmata and phloem, respectively, and may elicit symptoms in the infected host, with pathogenic pathways linked to RNA silencing and other plant defense responses. In this review, recent advances in the dissection of the complex interplay between viroids and plants are presented, highlighting knowledge gaps and perspectives for future research.
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New Insights into Chikungunya Virus Infection and Pathogenesis
Vol. 8 (2021), pp. 327–347More LessChikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus responsible for major outbreaks of disease since 2004 in the Indian Ocean islands, South east Asia, and the Americas. CHIKV causes debilitating musculoskeletal disorders in humans that are characterized by fever, rash, polyarthralgia, and myalgia. The disease is often self-limiting and nonlethal; however, some patients experience atypical or severe clinical manifestations, as well as a chronic rheumatic syndrome. Unfortunately, no efficient antivirals against CHIKV infection are available so far, highlighting the importance of deepening our knowledge of CHIKV host cell interactions and viral replication strategies. In this review, we discuss recent breakthroughs in the molecular mechanisms that regulate CHIKV infection and lay down the foundations to understand viral pathogenesis. We describe the role of the recently identified host factors co-opted by the virus for infection and pathogenesis, and emphasize the importance of CHIKV nonstructural proteins in both replication complex assembly and host immune response evasion.
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Conquering the Host: Determinants of Pathogenesis Learned from Murine Gammaherpesvirus 68
Vol. 8 (2021), pp. 349–371More LessGammaherpesviruses are an important class of oncogenic pathogens that are exquisitely evolved to their respective hosts. As such, the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV) do not naturally infect nonhuman primates or rodents. There is a clear need to fully explore mechanisms of gammaherpesvirus pathogenesis, host control, and immune evasion in the host. A gammaherpesvirus pathogen isolated from murid rodents was first reported in 1980; 40 years later, murine gammaherpesvirus 68 (MHV68, MuHV-4, γHV68) infection of laboratory mice is a well-established pathogenesis system recognized for its utility in applying state-of-the-art approaches to investigate virus-host interactions ranging from the whole host to the individual cell. Here, we highlight recent advancements in our understanding of the processes by which MHV68 colonizes the host and drives disease. Lessons that inform KSHV and EBV pathogenesis and provide future avenues for novel interventions against infection and virus-associated cancers are emphasized.
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Viruses and Metabolism: The Effects of Viral Infections and Viral Insulins on Host Metabolism
Vol. 8 (2021), pp. 373–391More LessOver the past decades, there have been tremendous efforts to understand the cross-talk between viruses and host metabolism. Several studies have elucidated the mechanisms through which viral infections manipulate metabolic pathways including glucose, fatty acid, protein, and nucleotide metabolism. These pathways are evolutionarily conserved across the tree of life and extremely important for the host's nutrient utilization and energy production. In this review, we focus on host glucose, glutamine, and fatty acid metabolism and highlight the pathways manipulated by the different classes of viruses to increase their replication. We also explore a new system of viral hormones in which viruses mimic host hormones to manipulate the host endocrine system. We discuss viral insulin/IGF-1-like peptides and their potential effects on host metabolism. Together, these pathogenesis mechanisms targeting cellular signaling pathways create a multidimensional network of interactions between host and viral proteins. Defining and better understanding these mechanisms will help us to develop new therapeutic tools to prevent and treat viral infections.
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Sex Differences in Respiratory Viral Pathogenesis and Treatments
Vol. 8 (2021), pp. 393–414More LessBiological sex affects the outcome of diverse respiratory viral infections. The pathogenesis of respiratory infections caused by viruses ranging from respiratory syncytial virus to influenza viruses and severe acute respiratory syndrome coronavirus 2 differs between the sexes across the life course. Generally, males are more susceptible to severe outcomes from respiratory viral infections at younger and older ages. During reproductive years (i.e., after puberty and prior to menopause), females are often at greater risk than males for severe outcomes. Pregnancy and biological sex affect the pathogenesis of respiratory viral infections. In addition to sex differences in the pathogenesis of disease, there are consistent sex differences in responses to treatments, with females often developing greater immune responses but experiencing more adverse reactions than males. Animal models provide mechanistic insights into the causes of sex differences in respiratory virus pathogenesis and treatment outcomes, where available.
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Bacteriophages and the Immune System
Vol. 8 (2021), pp. 415–435More LessBacteriophages—viruses that infect bacteria—are abundant within our bodies, but their significance to human health is only beginning to be explored. Here, we synthesize what is currently known about our phageome and its interactions with the immune system. We first review how phages indirectly affect immunity via bacterial expression of phage-encoded proteins. We next review how phages directly influence innate immunity and bacterial clearance. Finally, we discuss adaptive immunity against phages and its implications for phage/bacterial interactions. In light of these data, we propose that our microbiome can be understood as an interconnected network of bacteria, bacteriophages, and human cells and that the stability of these tri-kingdom interactions may be important for maintaining our immunologic and metabolic health. Conversely, the disruption of this balance, through exposure to exogenous phages, microbial dysbiosis, or immune dysregulation, may contribute to disease.
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Prospects for the Global Elimination of Hepatitis B
Vol. 8 (2021), pp. 437–458More LessChronic hepatitis B virus (HBV) infection is the leading cause of liver cirrhosis and hepatocellular carcinoma, estimated to be globally responsible for ∼800,000 deaths annually. Although effective vaccines are available to prevent new HBV infection, treatment of existing chronic hepatitis B (CHB) is limited, as the current standard-of-care antiviral drugs can only suppress viral replication without achieving cure. In 2016, the World Health Organization called for the elimination of viral hepatitis as a global public health threat by 2030. The United States and other nations are working to meet this ambitious goal by developing strategies to cure CHB, as well as prevent HBV transmission. This review considers recent research progress in understanding HBV pathobiology and development of therapeutics for the cure of CHB, which is necessary for elimination of hepatitis B by 2030.
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Small-Molecule Inhibition of Viral Fusion Glycoproteins
Vol. 8 (2021), pp. 459–489More LessViral fusion glycoproteins catalyze membrane fusion during viral entry. Unlike most enzymes, however, they lack a conventional active site in which formation or scission of a specific covalent bond is catalyzed. Instead, they drive the membrane fusion reaction by cojoining highly regulated changes in conformation to membrane deformation. Despite the challenges in applying inhibitor design approaches to these proteins, recent advances in knowledge of the structures and mechanisms of viral fusogens have enabled the development of small-molecule inhibitors of both class I and class II viral fusion proteins. Here, we review well-validated inhibitors, including their discovery, targets, and mechanism(s) of action, while highlighting mechanistic similarities and differences. Together, these examples make a compelling case for small-molecule inhibitors as tools for probing the mechanisms of viral glycoprotein-mediated fusion and for viral glycoproteins as druggable targets.
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The Current Status of Latency Reversing Agents for HIV-1 Remission
Vol. 8 (2021), pp. 491–514More LessCombinatory antiretroviral therapy (cART) reduces human immunodeficiency virus type 1 (HIV-1) replication but is not curative because cART interruption almost invariably leads to a rapid rebound of viremia due to the persistence of stable HIV-1-infected cellular reservoirs. These reservoirs are mainly composed of CD4+ T cells harboring replication-competent latent proviruses. A broadly explored approach to reduce the HIV-1 reservoir size, the shock and kill strategy, consists of reactivating HIV-1 gene expression from the latently infected cellular reservoirs (the shock), followed by killing of the virus-producing infected cells (the kill). Based on improved understanding of the multiple molecular mechanisms controlling HIV-1 latency, distinct classes of latency reversing agents (LRAs) have been studied for their efficiency to reactivate viral gene expression in in vitro and ex vivo cell models. Here, we provide an up-to-date review of these different mechanistic classes of LRAs and discuss optimizations of the shock strategy by combining several LRAs simultaneously or sequentially.
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FAST Proteins: Development and Use of Reverse Genetics Systems for Reoviridae Viruses
Vol. 8 (2021), pp. 515–536More LessReverse genetics systems for viruses, the technology used to generate gene-engineered recombinant viruses from artificial genes, enable the study of the roles of the individual nucleotides and amino acids of viral genes and proteins in infectivity, replication, and pathogenicity. The successful development of a reverse genetics system for poliovirus in 1981 accelerated the establishment of protocols for other RNA viruses important for human health. Despite multiple efforts, rotavirus (RV), which causes severe gastroenteritis in infants, was refractory to reverse genetics analysis, and the first complete reverse genetics system for RV was established in 2017. This novel technique involves use of the fusogenic protein FAST (fusion-associated small transmembrane) derived from the bat-borne Nelson Bay orthoreovirus, which induces massive syncytium formation. Co-transfection of a FAST-expressing plasmid with complementary DNAs encoding RV genes enables rescue of recombinant RV. This review focuses on methodological insights into the reverse genetics system for RV and discusses applications and potential improvements to this system.
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Virology in the Classroom: Current Approaches and Challenges to Undergraduate- and Graduate-Level Virology Education
Vol. 8 (2021), pp. 537–558More LessThe pervasive effects of the current coronavirus disease 2019 pandemic are but one reason for educators to refocus their efforts on virology teaching. Additionally, it is critical to understand how viruses function and to elucidate the relationship between virus and host. An understanding of current virology education may improve pedagogical approaches for educating our students and trainees. Faculty who teach undergraduate microbiology indicate that approximately 10% of the course content features viruses; stand-alone virology courses are infrequently offered to undergraduates. Fortunately, virology taught to undergraduates includes foundational material; several approaches for delivery of lecture- and lab-based content exist. At the graduate education level, there is growing appreciation that an emphasis on logic, reasoning, inference, and statistics must be reintroduced into the curriculum to create a generation of scientists who have a greater capacity for creativity and innovation. Educators also need to remove barriers to student success, at all levels of education.
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