Table of Contents
Spotlight
Structure and Assembly
Structure and AssemblyA Proteomic Atlas of the African Swine Fever Virus ParticleAfrican swine fever virus causes a highly contagious and lethal disease of swine that currently affects many countries of sub-Saharan Africa, the Caucasus, the Russian Federation, and Eastern Europe and has very recently spread to China. Despite extensive research, effective vaccines or antiviral strategies are still lacking, and many basic questions on the molecular mechanisms underlying the infective cycle remain. One such gap regards...
Structure and AssemblyMolecular Characterization of the Viroporin Function of Foot-and-Mouth Disease Virus Nonstructural Protein 2BFMDV nonstructural protein 2B is able to insert itself into cellular membranes to form a pore. This pore allows the passage of ions and small molecules through the membrane. In this study, we were able to show that both current and small molecules are able to pass though the pore made by 2B. We also discovered for the first time a virus with a pore-forming protein that contains two independent functional pores. By making mutations in...
Genome Replication and Regulation of Viral Gene Expression
Genome Replication and Regulation of Viral Gene ExpressionT5 Exonuclease Hydrolysis of Hepatitis B Virus Replicative Intermediates Allows Reliable Quantification and Fast Drug Efficacy Testing of Covalently Closed Circular DNA by PCRcccDNA elimination is a major goal in future curative regimens for chronic HBV patients. However, PCR-based assays for cccDNA quantification show a principally constrained specificity when high levels of input virus or replicative intermediates are present. Here, we characterized T5 exonuclease as a suitable enzyme for medium-throughput in vitro assays that preserves cccDNA but efficiently removes rcDNA prior to PCR-based...
Genome Replication and Regulation of Viral Gene ExpressionInterplay between the Poly(A) Tail, Poly(A)-Binding Protein, and Coronavirus Nucleocapsid Protein Regulates Gene Expression of Coronavirus and the Host CellGene expression in coronavirus is a complicated and dynamic process. In this study, we demonstrated that coronavirus N protein is able to bind to the poly(A) tail with high affinity, establishing N protein as a PABP. We also show how the interplay between coronavirus 3′ poly(A) tail, PABP, and N protein regulates gene expression of the coronavirus and host cell. Of the interactions, poly(A) tail binding by the N protein negatively...
Genome Replication and Regulation of Viral Gene ExpressionRobust Human and Murine Hepatocyte Culture Models of Hepatitis B Virus Infection and ReplicationHBV research has been greatly hampered by the lack of robust cell culture and small animal models of HBV infection and propagation. The discovery of NTCP as an HBV receptor has greatly impacted the field of HBV research. Although HBV infection of NTCP-expressing human and murine hepatocyte cell lines has been demonstrated, its replication in cell culture appeared inefficient. To further improve cell culture systems of HBV infection and...
Genetic Diversity and Evolution
Genetic Diversity and EvolutionDistribution, Diversity, and Evolution of Endogenous Retroviruses in Perissodactyl GenomesERVs in the host genome are highly informative about the long-term interactions of retroviruses and hosts. They are also interesting because they have influenced the evolution of mammalian genomes in various ways. In this study, we derive a calibrated timeline describing the process through which ERV diversity has been generated in the equine germ line. We determined the distribution and diversity of perissodactyl ERV lineages and...
Virus-Cell Interactions
Virus-Cell InteractionsThe Human Cytomegalovirus US27 Gene Product Constitutively Activates Antioxidant Response Element-Mediated Transcription through Gβγ, Phosphoinositide 3-Kinase, and Nuclear Respiratory Factor 1Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, causing deafness, blindness, and other serious birth defects. CXCR4 is a human chemokine receptor that is crucial for both fetal development and immune responses. We found that the HCMV protein US27 stimulates increased expression of CXCR4 through activation of the transcription factor nuclear respiratory factor 1 (NRF-1). NRF-1 regulates stress response...
Virus-Cell Interactions | SpotlightThe Nucleolar Protein LYAR Facilitates Ribonucleoprotein Assembly of Influenza A VirusInfluenza A virus (IAV) must utilize the host cell machinery to replicate, but many of the mechanisms of IAV-host interaction remain poorly understood. Improved understanding of interactions between host factors and vRNP not only increases our basic knowledge of the molecular mechanisms of virus replication and pathogenicity but also provides insights into possible novel antiviral targets that are necessary due to the widespread...
Virus-Cell InteractionsHost Enzymes Heparanase and Cathepsin L Promote Herpes Simplex Virus 2 Release from CellsGenital infections by HSV-2 represent one of the most common sexually transmitted viral infections. The virus causes painful lesions and sores around the genitals or rectum. Intermittent release of the virus from infected tissues during sexual activities is the most common cause of transmission. At the molecular level, cell surface heparan sulfate (HS) is known to provide attachment sites for HSV-2. While the removal of HS during HSV-1...
Virus-Cell InteractionsNSs Protein of Sandfly Fever Sicilian Phlebovirus Counteracts Interferon (IFN) Induction by Masking the DNA-Binding Domain of IFN Regulatory Factor 3Phleboviruses are receiving increased attention due to the constant discovery of new species and the ongoing spread of long-known members of the genus. Outbreaks of sandfly fever were reported in the 19th century, during World War I, and during World War II. Currently, SFSV is recognized as one of the most widespread phleboviruses, exhibiting high seroprevalence rates in humans and domestic animals and causing a self-limiting but...
Virus-Cell InteractionsStructure-Guided Identification of a Nonhuman Morbillivirus with Zoonotic PotentialA significant proportion of viral pandemics occur following zoonotic transmission events, where animal-associated viruses jump species into human populations. In order to provide forewarnings of the emergence of these viruses, it is necessary to develop a better understanding of what determines virus host range, often at the genetic and structural levels. In this study, we demonstrated that the small-ruminant morbillivirus, a close...
Virus-Cell InteractionsGlobal Analysis of Baculovirus Autographa californica Multiple Nucleopolyhedrovirus Gene Expression in the Midgut of the Lepidopteran Host Trichoplusia niBaculoviruses such as AcMNPV are pathogens that are natural regulators of certain insect populations. Baculovirus infections are biphasic, with a primary phase initiated by oral infection of midgut epithelial cells by occlusion-derived virus (ODV) virions and a secondary phase in which other tissues are infected by budded-virus (BV) virions. While AcMNPV infections in cultured cells have been studied extensively, comparatively little is...
Virus-Cell InteractionsRedundant Late Domain Functions of Tandem VP2 YPX3L Motifs in Nonlytic Cellular Egress of Quasi-enveloped Hepatitis A VirusNonlytic release of hepatitis A virus (HAV) as exosome-like quasi-enveloped virions is a unique but incompletely understood aspect of the hepatovirus life cycle. Several lines of evidence indicate that the host protein ALIX is essential for this process. Tandem YPX3L “late domains” in the VP2 capsid protein could be sites of interaction with ALIX, but they are not accessible on the surface of an X-ray model of the...
Virus-Cell Interactions | SpotlightDynamin-Like Proteins of Endocytosis in Plants Are Coopted by Potyviruses To Enhance Virus InfectionIt is well known that animal viruses enter host cells via endocytosis, whereas plant viruses require physical assistance, such as human and insect activities, to penetrate the host cell to establish their infection. In this study, we report that the endocytosis pathway is also involved in virus infection in plants. We show that plant potyviruses recruit endocytosis dynamin-like proteins to support their infection. Depletion of them by...
Virus-Cell InteractionsHuman Host Range Restriction of the Vaccinia Virus C7/K1 Double Deletion Mutant Is Mediated by an Atypical Mode of Translation InhibitionA dynamic relationship exists between viruses and their hosts in which each ostensibly attempts to exploit the other’s vulnerabilities. A window is opened into the established condition, which evolved over millennia, if loss-of-function mutations occur in either the virus or host. Thus, the inability of viral host range mutants to replicate in specific cells can be overcome by identifying and inactivating the opposing cellular gene....
Virus-Cell Interactions | SpotlightNovel Class of Viral Ankyrin Proteins Targeting the Host E3 Ubiquitin Ligase Cullin-2Viruses encode multiple proteins aimed at modulating cellular homeostasis and antagonizing the host antiviral response. Most of these genes were originally acquired from the host and subsequently adapted to benefit the virus. ANK proteins are common in eukaryotes but are unusual amongst viruses, with the exception of poxviruses, where they represent one of the largest protein families. We report here the existence of a new class of...
Virus-Cell InteractionsA Novel Chimeric Oncolytic Virus Vector for Improved Safety and Efficacy as a Platform for the Treatment of Hepatocellular CarcinomaThe therapeutic efficacy of oncolytic viral therapy often comes as a tradeoff with safety, such that potent vectors are often associated with toxicity, while safer viruses tend to have attenuated therapeutic effects. Despite promising preclinical data, the development of VSV as a clinical agent has been substantially hampered by the fact that severe neurotoxicity and hepatotoxicity have been observed in rodents and nonhuman primates in...
Virus-Cell InteractionsSindbis Virus Infection Causes Cell Death by nsP2-Induced Transcriptional Shutoff or by nsP3-Dependent Translational ShutoffAlphaviruses are a group of important human and animal pathogens with worldwide distribution. Their characteristic feature is a highly cytopathic phenotype in cells of vertebrate origin. The molecular mechanism of CPE remains poorly understood. In this study, by using Sindbis virus (SINV) as a model of the Old World alphaviruses, we demonstrated that SINV-specific CPE is redundantly determined by viral nsP2 and nsP3 proteins. NsP2...
Virus-Cell InteractionsExpression of Human Cytomegalovirus IE1 Leads to Accumulation of Mono-SUMOylated PML That Is Protected from Degradation by Herpes Simplex Virus 1 ICP0Our finding that HCMV IE1 protected hPML from degradation by HSV ICP0 is important, because the PML body (aka ND10) is believed to be the first line of host intrinsic defense against herpesviral infection. How the infected viruses overcome the nuclear defensive structure (PML body) has not been fully understood. Herpesviral proteins, ICP0 of HSV and IE1 of CMV, have been identified to interact with PML. Here, we report that HCMV IE1...
Virus-Cell InteractionsCellular Protein Kinase D Modulators Play a Role during Multiple Steps of Herpes Simplex Virus 1 EgressViruses are obligatory parasites that highjack numerous cellular functions. This is certainly true when it comes to transporting viral particles within the cell. Herpesviruses share the unique property of traveling through the two nuclear membranes by subsequent budding and fusion and acquiring their final envelope from a cellular organelle. Albeit disputed, the overall evidence from many laboratories points to the trans-Golgi...
Cellular Response to Infection
Cellular Response to InfectionModulation of Vaccine-Induced CD4 T Cell Functional Profiles by Changes in Components of HIV Vaccine Regimens in HumansOnly one HIV-1 candidate vaccine strategy has shown protection, albeit marginally (31%), against HIV-1 acquisition, and correlates of protection suggested that a multifunctional CD4 T cell immune response may be important for this protective effect. Therefore, the functional phenotypes of HIV-specific CD4 T cell responses induced by different phase I and phase II clinical trials were assessed to better show how different vaccine...
Cellular Response to Infection | SpotlightToll-Like Receptor 7 (TLR-7) and TLR-9 Agonists Improve Hepatitis C Virus Replication and Infectivity Inhibition by Plasmacytoid Dendritic CellsWe implemented a coculture system of pDCs with HCV-infected hepatoma cell line, Huh7.5. We used three HCV derivatives in order to gain insight into pDCs’ behavior against HCV and associated antiviral mechanisms. The results with this cell coculture system support the capacity of pDCs to inhibit HCV replication and infectivity mainly via IFN-α, but also through additional mechanisms associated with pDC maturation. We provided evidence...
Cellular Response to InfectionHOIL1 Is Essential for the Induction of Type I and III Interferons by MDA5 and Regulates Persistent Murine Norovirus InfectionHuman noroviruses are a leading cause of gastroenteritis throughout the world but are challenging to study in vivo and in vitro. Murine norovirus (MNoV) provides a tractable genetic and small-animal model to study norovirus biology and immune responses. Interferons are critical mediators of antiviral immunity, but excessive expression can dysregulate the immune system. IFN-λ plays an important role at mucosal surfaces...
Cellular Response to InfectionA Single Point Mutation in the Rhinovirus 2B Protein Reduces the Requirement for Phosphatidylinositol 4-Kinase Class III Beta in Viral ReplicationHuman rhinoviruses (RVs) are the major cause of the common cold worldwide. They cause asthmatic exacerbations and chronic obstructive pulmonary disease. Despite recent advances, the development of antivirals and vaccines has proven difficult due to the high number and variability of RV types. The identification of critical host factors and their interactions with viral proteins and membrane lipids for the establishment of viral...
Transformation and Oncogenesis
Transformation and OncogenesisEpstein-Barr Virus MicroRNA miR-BART5-3p Inhibits p53 ExpressionEBV encodes 44 mature microRNAs, which have been proven to promote EBV-associated diseases by targeting host genes and self-viral genes. In EBV-associated carcinomas, the expression of viral protein is limited but the expression of BART microRNAs is extremely high, suggesting that they could be major factors in the contribution of EBV-associated tumorigenesis. p53 is a critical tumor suppressor. Unlike in most human solid tumors, TP53...
Vaccines and Antiviral Agents
Vaccines and Antiviral AgentsCharacterization of Antibody Interactions with the G Protein of Vesicular Stomatitis Virus Indiana Strain and Other Vesiculovirus G ProteinsVSVind.G is currently regarded as the gold-standard envelope glycoprotein to pseudotype lentiviral vectors. However, recently other G proteins derived from vesiculoviruses have been proposed as alternative envelopes. Here, we investigated two commercially available anti-VSVind.G monoclonal antibodies for their ability to cross-react with other vesiculovirus G proteins, identified the epitopes they recognize, and explored their...
Vaccines and Antiviral AgentsRecombinant Infectious Bronchitis Viruses Expressing Chimeric Spike Glycoproteins Induce Partial Protective Immunity against Homologous Challenge despite Limited Replication In VivoInfectious bronchitis virus causes an acute, highly contagious respiratory disease, responsible for significant economic losses to the poultry industry. Amino acid differences in the surface protein, spike (S), in particular the S1 subunit, have been associated with poor cross-protection. Available vaccines give poor cross-protection and rationally designed live attenuated vaccines, based on apathogenic BeauR, could address these. Here...
Pathogenesis and Immunity
Pathogenesis and ImmunityPotent Neutralizing Human Monoclonal Antibodies Preferentially Target Mature Dengue Virus Particles: Implication for Novel Strategy for Dengue VaccineWith an estimated 390 million infections per year, the four serotypes of dengue virus (DENV) cause the most important mosquito-borne viral disease in humans. The dengue vaccine Dengvaxia was licensed; however, its low efficacy among dengue-naive individuals and increased risk of causing severe dengue in children highlight the need for a better understanding of the role of human antibodies in immunity against DENV. DENV suspensions...
Pathogenesis and Immunity | SpotlightNatural Secretory Immunoglobulins Promote Enteric Viral InfectionsEnteric virus, such as norovirus, infections cause significant morbidity and mortality worldwide. However, direct antiviral infection prevention strategies are limited. Blocking host entry and initiation of infection provides an established avenue for intervention. Here, we investigated the role of the polymeric immunoglobulin receptor (pIgR)-secretory immunoglobulin (sIg) cycle during enteric virus infections. The innate immune...
Pathogenesis and ImmunityAttenuation of Influenza A Virus Disease Severity by Viral Coinfection in a Mouse ModelViral infections in the respiratory tract can cause severe disease and are responsible for a majority of pediatric hospitalizations. Molecular diagnostics have revealed that approximately 20% of these patients are infected by more than one unrelated viral pathogen. To understand how viral coinfection affects disease severity, we inoculated mice with a mild viral pathogen (rhinovirus or murine coronavirus), followed 2 days later by a...
Pathogenesis and ImmunitySusceptibility to Neutralization by Broadly Neutralizing Antibodies Generally Correlates with Infected Cell Binding for a Panel of Clade B HIV Reactivated from Latent ReservoirsAlthough antiretroviral therapies have improved the lives of people who are living with HIV, they do not cure infection. Efforts are being directed towards harnessing the immune system to eliminate the virus that persists, potentially resulting in virus-free remission without medication. HIV-specific antibodies hold promise for such therapies owing to their ability to both prevent the infection of new cells (neutralization) and direct...
Pathogenesis and ImmunityReovirus Neurotropism and Virulence Are Dictated by Sequences in the Head Domain of the Viral Attachment ProteinViral encephalitis is a serious and often life-threatening inflammation of the brain. Mammalian orthoreoviruses are promising oncolytic therapeutics for humans but establish virulent, serotype-dependent disease in the central nervous system (CNS) of many young mammals. Serotype 1 reoviruses infect ependymal cells and produce hydrocephalus, whereas serotype 3 reoviruses infect neurons and cause encephalitis. Reovirus neurotropism is...
Pathogenesis and ImmunityType I Interferon Signaling Prevents Hepatitis B Virus-Specific T Cell Responses by Reducing Antigen ExpressionHepatitis B virus (HBV) causes acute and chronic infection, and approximately 240 million people are chronically infected with HBV worldwide. It is generally believed that virus-specific CD8+ T cell responses are required for the clearance of HBV. However, the relative contributions of genetic variation and innate immune responses to the induction of HBV-specific CD8+ T cell responses are not fully understood. In...
Pathogenesis and ImmunityHepatitis B Spliced Protein (HBSP) Suppresses Fas-Mediated Hepatocyte Apoptosis via Activation of PI3K/Akt SignalingOur study revealed a previously unappreciated role of HBSP in Fas-mediated apoptosis. The antiapoptotic activity of HBSP is important for understanding hepatitis B virus pathogenesis. In particular, HBV variants associated with hepatoma carcinoma may downregulate apoptosis of hepatocytes through enhanced HBSP expression. Our study also found that Akt is centrally involved in Fas-induced hepatocyte apoptosis and revealed that...
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