Table of Contents
Spotlight
Gem
GemImpact of Replication Stress in Human Papillomavirus PathogenesisThe inactivation of critical cell cycle checkpoints by the human papillomavirus (HPV) oncoprotein E7 results in replication stress (RS) that leads to genomic instability in premalignant lesions. Intriguingly, RS tolerance is achieved through several mechanisms, enabling HPV to exploit the cellular RS response for viral replication and to facilitate viral persistence in the presence of DNA damage.
Structure and Assembly
Structure and AssemblyIsolation of Neutralizing Monoclonal Antibodies to Human Astrovirus and Characterization of Virus Variants That Escape NeutralizationHuman astroviruses (HAstVs) are common etiological agents of acute gastroenteritis in children, the elderly, and immunocompromised patients; some virus strains have also been associated with neurological disease. Despite their medical importance, the study of these pathogens has advanced at a slow pace. In this work, we produced neutralizing antibodies to the virus and mapped the epitopes they recognize on the virus capsid. These...
Structure and AssemblyEncapsidation of Viral RNA in Picornavirales: Studies on Cowpea Mosaic Virus Demonstrate Dependence on Viral ReplicationThe mechanism whereby members of the order Picornavirales specifically package their genomic RNAs is poorly understood. Research with monopartite members of the order, such as poliovirus, indicated that packaging is linked to replication, although the presence of “packaging signals” along the length of the viral RNA has also been suggested. Thanks to the bipartite nature of the CPMV genome, which allows the manipulation of RNA-...
Structure and AssemblyStructural Basis for Human Norovirus Capsid Binding to Bile AcidsGiven that human norovirus virions likely interact with bile acid during a natural infection, our evidence that an HBGA nonbinder (GII.1) can be converted to an HBGA binder after bile acid binding is of major significance. Our data provide direct evidence that, like HBGAs, bile acid interaction on the capsid is an important cofactor for certain genotypes. However, more unanswered questions seem to arise from these new discoveries. For...
Structure and AssemblyComponents of the Reovirus Capsid Differentially Contribute to StabilityNonenveloped and enveloped viruses are exposed to the environment during transmission to a new host. Protein-protein and/or protein-lipid interactions stabilize the particle and protect the viral genome. Mammalian orthoreovirus (reovirus) is composed of two concentric, protein shells. The μ1 and σ3 proteins form the outer capsid; contacts between neighboring subunits are thought to confer resistance to inactivating agents. We further...
Genome Replication and Regulation of Viral Gene Expression
Genome Replication and Regulation of Viral Gene ExpressionInhibition of Epstein-Barr Virus Replication in Human Papillomavirus-Immortalized KeratinocytesUsing a model examining the establishment of EBV infection in HPV-immortalized tissues, we showed an HPV-induced interruption of the normal EBV life cycle reminiscent of a latent EBV infection. Our data support the notion that a persistent EBV epithelial infection depends upon preexisting cellular alterations and suggest the ability of HPV to promote such changes. More importantly, these findings introduce a model for how EBV...
Genome Replication and Regulation of Viral Gene Expression | SpotlightMinute Virus of Canines NP1 Protein Interacts with the Cellular Factor CPSF6 To Regulate Viral Alternative RNA ProcessingThe Parvovirinae are small nonenveloped icosahedral viruses that are important pathogens in many animal species, including humans. Unlike other parvoviruses, the bocavirus genus controls expression of its capsid proteins via alternative RNA processing, by both suppressing polyadenylation at an internal site, termed the proximal polyadenylation (pA)p site, and by facilitating splicing of an upstream adjacent intron. This...
Genome Replication and Regulation of Viral Gene ExpressionA Genome-Wide Epstein-Barr Virus Polyadenylation Map and Its Antisense RNA to EBNAEpstein-Barr virus represents an important human pathogen with an etiological role in the development of several cancers. By elucidation of a genome-wide polyadenylation landscape of EBV in JSC-1, Raji, and Akata cells, we have redefined the EBV transcriptome and mapped individual polymerase II (Pol II) transcripts of viral genes to each one of the mapped pA sites at single-nucleotide resolution as well as the depth of expression. By...
Genome Replication and Regulation of Viral Gene ExpressionGroup A Rotavirus VP1 Polymerase and VP2 Core Shell Proteins: Intergenotypic Sequence Variation and In Vitro Functional CompatibilityGroup A rotaviruses (RVAs) are widespread in nature, infecting numerous mammalian and avian hosts and causing severe gastroenteritis in human children. RVAs are classified using a system that assigns a genotype to each viral gene according to its nucleotide sequence. To date, 22 genotypes have been described for the gene encoding the viral polymerase (VP1), and 20 genotypes have been described for the gene encoding the core shell...
Genetic Diversity and Evolution
Genetic Diversity and EvolutionMetagenomic Sequencing of HIV-1 in the Blood and Female Genital Tract Reveals Little Quasispecies Diversity during Acute InfectionDue to error-prone replication, HIV-1 generates a diverse population of viruses within a chronically infected individual. When HIV-1 is transmitted to a new individual, one or a few viruses establish the new infection, leading to a genetic bottleneck in the virus population. Understanding the timing and nature of this bottleneck may provide insight into HIV-1 vaccine design and other preventative strategies. We examined the HIV-1...
Genetic Diversity and Evolution | SpotlightEurasian Avian-Like Swine Influenza A Viruses Escape Human MxA Restriction through Distinct Mutations in Their NucleoproteinThe human MxA protein efficiently blocks the replication of IAV from nonhuman species. In rare cases, however, these IAV overcome the species barrier and become pandemic. All known pandemic viruses have acquired and maintained MxA escape mutations in the viral NP and thus are not efficiently controlled by MxA. Intriguingly, partial MxA resistance can also be acquired in other hosts that express antivirally active Mx proteins, such as...
Genetic Diversity and EvolutionIsolation and Characterization of a Distinct Influenza A Virus from Egyptian BatsThrough surveillance, we isolated and characterized an influenza A virus from Egyptian fruit bats. This virus had an affinity to avian-like receptors but was also able to infect mice. Our findings indicate that bats may harbor a diversity of influenza A viruses. Such viruses may have the potential to cross the species barrier to infect other species, including domestic birds, mammals, and, possibly, humans.
Genetic Diversity and EvolutionPlasticity of Amino Acid Residue 145 Near the Receptor Binding Site of H3 Swine Influenza A Viruses and Its Impact on Receptor Binding and Antibody RecognitionThe complex and continuous antigenic evolution of IAVs remains a major hurdle for vaccine selection and effective vaccination. On the hemagglutinin (HA) of the H3N2 IAVs, the amino acid substitution N 145 K causes significant antigenic changes. We show that amino acid 145 displays remarkable amino acid plasticity in vitro, tolerating multiple amino acid substitutions, many of which have not yet been observed in nature. Mutant...
Virus-Cell Interactions
Virus-Cell Interactions | SpotlightHepatitis B e Antigen Inhibits NF-κB Activity by Interrupting K63-Linked Ubiquitination of NEMOThe role of HBeAg in inflammatory responses during the infection of hepatitis B virus (HBV) is not fully understood, and several previous reports with regard to the NF-κB pathway are controversial. In this study, we showed that HBeAg could suppress both Toll-like receptor 2 (TLR2)- and IL-1β-induced activation of NF-κB in cells and clinical samples, and we further revealed novel molecular mechanisms. We found that HBeAg can associate...
Virus-Cell InteractionsFoot-and-Mouth Disease Virus Leader Protease Cleaves G3BP1 and G3BP2 and Inhibits Stress Granule FormationThe picornavirus foot-and-mouth disease virus (FMDV) is a notorious animal pathogen that puts a major economic burden on the global livestock industry. Outbreaks have significant consequences for animal health and product safety. Like many other viruses, FMDV must manipulate antiviral host responses to establish infection. Upon infection, viral double-stranded RNA (dsRNA) is detected, which results in the activation of the RNA-dependent...
Virus-Cell InteractionsHepatitis C Virus Downregulates Ubiquitin-Conjugating Enzyme E2S Expression To Prevent Proteasomal Degradation of NS5A, Leading to Host Cells More Sensitive to DNA DamageProtein homeostasis is essential to normal cell function. HCV infection disturbs the protein homeostasis in the host cells. Therefore, host cells exert an anti-HCV activity in order to maintain normal cellular metabolism. We showed that UBE2S interacted with HCV NS5A and degraded NS5A protein through the Lys11-linked proteasome-dependent pathway. However, HCV has evolved to overcome host antiviral activity. We demonstrated that the...
Virus-Cell InteractionsA MicroRNA Derived from Adenovirus Virus-Associated RNAII Promotes Virus Infection via Posttranscriptional Gene SilencingSeveral types of viruses encode viral miRNAs which regulate host and/or viral gene expression via posttranscriptional gene silencing, leading to efficient viral infection. Adenovirus (Ad) expresses miRNAs derived from VA-RNAs (mivaRNAI and -II); however, recent studies have revealed that processing of VA-RNAI into mivaRNAI inhibits Ad replication. Conversely, we demonstrate here that mivaRNAII significantly promotes Ad replication and...
Virus-Cell InteractionsMutations in the Spike Protein of Middle East Respiratory Syndrome Coronavirus Transmitted in Korea Increase Resistance to Antibody-Mediated NeutralizationMERS-CoV has pandemic potential, and it is important to identify mutations in viral proteins that might augment viral spread. In the course of a large hospital outbreak of MERS in the Republic of Korea in 2015, the spread of a viral variant that contained mutations in the viral spike protein was observed. These mutations were found to reduce receptor binding and viral infectivity. However, it remained unclear whether they also exerted...
Virus-Cell InteractionsMurine Leukemia Virus Glycosylated Gag Reduces Murine SERINC5 Protein Expression at Steady-State Levels via the Endosome/Lysosome Pathway to Counteract SERINC5 Antiretroviral ActivityMLV glycoGag not only enhances MLV replication but also increases HIV-1 infectivity similarly as Nef. Recent studies have discovered that both glycoGag and Nef antagonize a novel host restriction factor Ser5 and promote viral replication. Compared to Nef, the glycoGag antagonism of Ser5 is still poorly understood. MLV glycoGag is a transmembrane version of the structural Gag protein with an extra 88-amino-acid leader region that...
Virus-Cell Interactions | SpotlightHIV-1 Antisense Protein of Different Clades Induces Autophagy and Associates with the Autophagy Factor p62In the present study, we provide the first evidence that a new HIV-1 protein termed ASP derived from different clades acts similarly in inducing autophagy, an important cellular process implicated in the degradation of excess or defective cellular material. We have gained further knowledge on the mechanism mediating the activation of autophagy. Our studies have important ramifications in the understanding of viral replication and the...
Virus-Cell InteractionsSelective Editing of Herpes Simplex Virus 1 Enables Interferon Induction and Viral Replication That Destroy Malignant CellsOncolytic herpes simplex virus 1 is a promising agent for cancer immunotherapy. Due to a complex virus-host interaction, less is clear about what viral signature(s) constitutes a potent oncolytic backbone. Through molecular or genetic dissection, we showed that selective editing of the γ134.5 gene enables viral replication in malignant cells, activation of transcription factor IRF3, and subsequent induction of type I IFN....
Virus-Cell InteractionsThe NS1 Protein of Influenza A Virus Participates in Necroptosis by Interacting with MLKL and Increasing Its Oligomerization and Membrane TranslocationNecroptosis is a programmed cell death that is inflammatory in nature owing to the release of danger-associated molecular patterns from the ruptured cell membrane. However, necroptosis also constitutes an important arm of host immune responses. Thus, a balanced inflammatory response determines the disease outcome. We report that the NS1 protein of IAV participates in necroptosis by interacting with MLKL, resulting in increased MLKL...
Virus-Cell InteractionsLow-pH Endocytic Entry of the Porcine Alphaherpesvirus Pseudorabies VirusPRV is a pathogen of great economic and animal welfare importance in many parts of the world. PRV causes neurological, respiratory, and reproductive disorders, often resulting in mortality of young and immunocompromised animals. Mortality, decreased production, and trade restrictions result in significant financial losses for the agricultural industry. Understanding the molecular mechanisms utilized by PRV to enter host cells is an...
Virus-Cell InteractionsBiogenesis of Extracellular Vesicles during Herpes Simplex Virus 1 Infection: Role of the CD63 TetraspaninIntercellular communication, especially in neurons, largely relies on EVs, and modulation of EVs is known to impact physiological processes. Here, we present evidence that HSV-1 infection causes major alterations in the biogenesis of EVs, including an increase in their number and an increase in the CD63-positive population of EVs. These alterations result in an enrichment of the milieu of infection with EVs carrying signatures from...
Cellular Response to Infection
Cellular Response to InfectionDynamics of Virus-Specific Memory B Cells and Plasmablasts following Viral Infection of the Central Nervous SystemThe prevalence and role of antigen-specific Bmem in the CNS during viral encephalomyelitis is largely undefined. A lack of reliable markers identifying murine Bmem has made it difficult to assess their contribution to local antiviral protection via antigen presentation or conversion to ASC. Using reporter mice infected with neurotropic coronavirus to track virus-specific Bmem and ASC, this report demonstrates that both subsets only...
Cellular Response to InfectionReleased Tryptophanyl-tRNA Synthetase Stimulates Innate Immune Responses against Viral InfectionARSs are essential enzymes in translation that link specific amino acids to their cognate tRNAs. In higher eukaryotes, some ARSs possess additional, noncanonical functions in the regulation of cell metabolism. Here, we report a novel noncanonical function of WRS in antiviral defense. WRS is rapidly secreted in response to viral infection and primes the innate immune response by inducing the secretion of proinflammatory cytokines and...
Cellular Response to InfectionDUSP10 Negatively Regulates the Inflammatory Response to Rhinovirus through Interleukin-1β SignalingRhinoviruses are one of the causes of the common cold. In patients with asthma or chronic obstructive pulmonary disease, viral infections, including those with rhinovirus, are the commonest cause of exacerbations. Novel therapeutics to limit viral inflammation are clearly required. The work presented here identifies DUSP10 as an important protein involved in limiting the inflammatory response in the airway without affecting immune...
Cellular Response to InfectionFunctional Mapping of Regions Involved in the Negative Imprinting of Virion Particle Infectivity and in Target Cell Protection by Interferon-Induced Transmembrane Protein 3 against HIV-1IFITM proteins have been associated with the sequestration of incoming virions in endosomes (target cell protection) and with the production of virion particles that incorporate IFITMs and exhibit decreased infectivity (negative imprinting of virion infectivity). How the latter is regulated and whether these two antiviral properties are related remain unknown. By examining the behavior of a large panel of IFITM3 mutants against HIV-1,...
Vaccines and Antiviral Agents
Vaccines and Antiviral AgentsBCL6 Inhibitor-Mediated Downregulation of Phosphorylated SAMHD1 and T Cell Activation Are Associated with Decreased HIV Infection and ReactivationThe expansion and accumulation of HIV-infected BCL6+ Tfh CD4+ T cells are thought to contribute to the persistence of viral reservoirs in infected subjects undergoing ART. Two mechanisms have been raised for the preferential retention of HIV within Tfh CD4+ T cells: (i) antiretroviral drugs have limited tissue distribution, resulting in insufficient tissue concentration and lower efficacy in controlling...
Vaccines and Antiviral AgentsDolutegravir Monotherapy of Simian Immunodeficiency Virus-Infected Macaques Selects for Several Patterns of Resistance Mutations with Variable Virological OutcomesA growing number of anti-HIV drug combinations are effective in suppressing virus replication in HIV-infected persons. However, to reduce their cost and risk for toxicity, there is considerable interest in simplifying drug regimens. A major concern with single-drug regimens is the emergence of drug-resistant viral mutants. It has been speculated that DTG monotherapy may be a feasible option, because DTG may have a higher genetic barrier...
Vaccines and Antiviral AgentsDetermining the Mutation Bias of Favipiravir in Influenza Virus Using Next-Generation SequencingNew antiviral drugs are needed as a first line of defense in the event of a novel influenza pandemic. Favipiravir is a broad-spectrum antiviral which is effective against influenza. The exact mechanism of how favipiravir works to inhibit influenza is still unclear. We used next-generation sequencing (NGS) to demonstrate that favipiravir causes mutations in influenza RNA. The greater depth of NGS sequence information over traditional...
Vaccines and Antiviral AgentsSensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over TimeMajor progress occurred during the last decade leading to the isolation of human monoclonal antibodies, termed broadly neutralizing antibodies (bnAbs) due to their capacity to neutralize various strains of HIV-1. Several clinical trials are under way in order to evaluate their efficacy in preventive or therapeutic strategies. However, no single bnAb is active against 100% of strains. It is important to gather data on the sensitivity to...
Vaccines and Antiviral AgentsMutations in Influenza A Virus Neuraminidase and Hemagglutinin Confer Resistance against a Broadly Neutralizing Hemagglutinin Stem AntibodyInfluenza A virus is a public health threat for which currently available vaccines are not always effective. Broadly neutralizing antibodies that bind to the highly conserved stem region of the influenza virus hemagglutinin (HA) can neutralize many influenza virus strains. To understand how influenza virus can become resistant or escape such antibodies, we propagated influenza A virus in vitro with escalating concentrations of...
Vaccines and Antiviral AgentsAntibody Responses toward the Major Antigenic Sites of Influenza B Virus Hemagglutinin in Mice, Ferrets, and HumansThis study dissected the specific antibody responses toward the major antigenic sites and the noncanonical epitopes of influenza B virus hemagglutinin in animals and humans using novel reagents. These findings will guide the design of the next generation of influenza virus vaccines.
Vaccines and Antiviral AgentsN-Glycosylation of Seasonal Influenza Vaccine Hemagglutinins: Implication for Potency Testing and Immune ProcessingIn the present study, the glycosylation patterns of the 2014-2015 influenza vaccine season standard antigens A/California/07/2009 H1N1, A/Texas/50/2012 H3N2, and B/Massachusetts/02/2012 were revealed, and the sensitivity of the single radial immunodiffusion (SRID) potency test to glycosylation was tested. Differences in hemagglutinin glycosylation site composition and heterogeneity seen in antigens produced in different cell substrates...
Pathogenesis and Immunity
Pathogenesis and ImmunityMutation of Influenza A Virus PA-X Decreases Pathogenicity in Chicken Embryos and Can Increase the Yield of Reassortant Candidate Vaccine VirusesInfluenza A virus is a widespread pathogen that affects both humans and a variety of animal species, causing regular epidemics and sporadic pandemics, with major public health and economic consequences. A better understanding of virus biology is therefore important. The primary control measure is vaccination, which for humans mostly relies on antigens produced in eggs from PR8-based viruses bearing the glycoprotein genes of interest....
Pathogenesis and ImmunityAcute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus MacaquesHerpes simplex virus 2 (HSV-2) infects nearly 500 million persons globally, with an estimated 21 million incident cases each year, making it one of the most common sexually transmitted infections (STIs). HSV-2 is associated with increased human immunodeficiency virus type 1 (HIV-1) acquisition, and this risk does not decline with the use of antiherpes drugs. As initial acquisition of both HIV and HSV-2 infections is subclinical, study...
Pathogenesis and Immunity | SpotlightAbsence of β6 Integrin Reduces Influenza Disease Severity in Highly Susceptible Obese MiceObesity is a risk factor for developing severe influenza virus infection. However, the reasons for this are unknown. We found that the lungs of obese mice have increased expression of the epithelial integrin β6, a host factor associated with increased disease severity. Knocking out integrin β6 in obese mice favorably altered the pulmonary environment by increasing type I IFN signaling, resulting in decreased viral spread, reduced lung...
Pathogenesis and ImmunityDeletion of both the Tyrosine-Based Endocytosis Signal and the Endoplasmic Reticulum Retrieval Signal in the Cytoplasmic Tail of Spike Protein Attenuates Porcine Epidemic Diarrhea Virus in PigsMany coronaviruses (CoVs) possess conserved motifs YxxΦ and/or KxHxx/KKxx in the cytoplasmic tail of the S protein. The KxHxx/KKxx motif has been identified as the ER retrieval signal, but the function of the YxxΦ motif in the intracellular sorting of CoV S proteins remains controversial. In this study, we showed that the YxxΦ of PEDV S protein is an endocytosis signal. Furthermore, using reverse genetics technology, we evaluated its...
Pathogenesis and ImmunityHuman Norovirus Epitope D Plasticity Allows Escape from Antibody Immunity without Loss of Capacity for Binding Cellular LigandsHuman norovirus causes ∼20% of all acute gastroenteritis and ∼200,000 deaths per year, primarily in young children. Most epidemic and all pandemic waves of disease over the past 30 years have been caused by type GII.4 human norovirus strains. The capsid sequence of GII.4 strains is changing over time, resulting in viruses with altered ligand and antibody binding characteristics. The carbohydrate binding pocket of these strains does not...
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