Spotlight
Structure and Assembly
Structure and AssemblyStructural Differences between the Woodchuck Hepatitis Virus Core Protein in the Dimer and Capsid States Are Consistent with Entropic and Conformational Regulation of AssemblyVirus capsids assemble spontaneously with surprisingly high fidelity. This requires strict geometry and a narrow range of association energies for these protein-protein interactions. It was hypothesized that requiring subunits to undergo a conformational change to become assembly active could regulate assembly by creating an energetic barrier and attenuating association. We found that woodchuck hepatitis virus capsid protein undergoes...
Structure and AssemblyRoles of the Interhexamer Contact Site for Hexagonal Lattice Formation of the Herpes Simplex Virus 1 Nuclear Egress Complex in Viral Primary Envelopment and ReplicationThe scaffolding proteins of several envelope viruses required for virion assembly form high-order lattice structures. However, information on the significance of their lattice formation in infected cells is limited. Herpesviruses acquire envelopes twice during their viral replication. The first envelop acquisition (primary envelopment) is one of the steps in the vesicle-mediated nucleocytoplasmic transport of nascent nucleocapsids,...
Structure and AssemblyA Hydrophobic Network: Intersubunit and Intercapsomer Interactions Stabilizing the Bacteriophage P22 CapsidSimilarities in assembly reactions and coat protein structures of the dsDNA tailed phages and herpesviruses make phages ideal models to understand capsid assembly and identify potential targets for antiviral drug discovery. The coat protein E-loops of these viruses are involved in both intra- and intercapsomer interactions. In phage P22, hydrophobic interactions peg the coat protein subunits together within a capsomer, where the E-loop...
Genome Replication and Regulation of Viral Gene Expression
Genome Replication and Regulation of Viral Gene ExpressionPicornavirus RNA Recombination Counteracts Error CatastrophePositive-strand RNA viruses produce vast amounts of progeny in very short periods of time via template-dependent RNA replication mechanisms. Template-dependent RNA replication, while efficient, can be disadvantageous due to error-prone viral polymerases. The accumulation of mutations in viral RNA genomes leads to error catastrophe. In this study, we substantiate long-held theories regarding the advantages and disadvantages of asexual...
Genome Replication and Regulation of Viral Gene ExpressionA Noncanonical Basic Motif of Epstein-Barr Virus ZEBRA Protein Facilitates Recognition of Methylated DNA, High-Affinity DNA Binding, and Lytic ActivationThe binding of ZEBRA to methylated and unmethylated viral DNA triggers activation of the EBV lytic cycle, leading to viral replication and, in some patients, cancer development. Our work thoroughly examines how ZEBRA uses a previously unrecognized basic motif to bind nonmethylated and methylated DNA targets, leading to viral lytic activation. Our findings show that two different positively charged motifs, including the canonical BZIP...
Genetic Diversity and Evolution
Genetic Diversity and EvolutionDiscovery of Novel Crustacean and Cephalopod Flaviviruses: Insights into the Evolution and Circulation of Flaviviruses between Marine Invertebrate and Vertebrate HostsSome flaviviruses are known to cause disease in vertebrates and are typically transmitted by blood-feeding arthropods such as ticks and mosquitoes. While an ever-increasing number of insect-specific flaviviruses have been described, we have a narrow understanding of flavivirus incidence and evolution. To expand this understanding, we discovered a number of novel flaviviruses that infect a range of crustaceans and cephalopod hosts....
Genetic Diversity and EvolutionAttenuation of Infectious Bronchitis Virus in Eggs Results in Different Patterns of Genomic Variation across Multiple ReplicatesInfectious bronchitis remains a major problem in the global poultry industry, despite the existence of many different vaccines. IBV vaccines are currently developed by serial passage of a virulent strain on embryonated hen’s eggs until attenuation; however, little is known about the evolution of the viral population during the process of attenuation. High-throughput sequencing of four replicates of a serially egg-passaged IBV revealed a...
Genetic Diversity and Evolution | SpotlightSingle-Cell Virus Sequencing of Influenza Infections That Trigger Innate ImmunityBecause influenza virus has a high mutation rate, many cells are infected by mutated virions. But so far, it has been impossible to fully characterize the sequence of the virion infecting any given cell, since conventional techniques such as flow cytometry and single-cell transcriptome sequencing (scRNA-seq) only detect if a protein or transcript is present, not its sequence. Here we develop a new approach that uses long-read PacBio...
Genetic Diversity and EvolutionConvergent Co-option of the Retroviral gag Gene during the Early Evolution of MammalsRetroviruses occasionally can infect host germ lines, forming endogenous retroviruses. Vertebrates, in turn, recruited retroviral genes for their own biological functions, a process formally known as co-option or exaptation. To date, co-opted retroviral gag genes have rarely been reported. In this study, we identified two co-opted retroviral gag genes, designated wucaishi1 (wcs1) and wucaishi2...
Virus-Cell Interactions
Virus-Cell Interactions | SpotlightBK Polyomavirus Activates the DNA Damage Response To Prolong S PhaseBK polyomavirus (BKPyV) is an emerging pathogen that reactivates in immunosuppressed organ transplant patients. We wanted to understand why BKPyV-induced activation of the DNA damage response (DDR) enhances viral titers and prevents host DNA damage. Here, we show that the virus activates the DNA damage response in order to keep the infected cells in S phase to replicate the viral DNA. The source of DNA damage was due to actively...
Virus-Cell InteractionsHost-Specific NS5 Ubiquitination Determines Yellow Fever Virus TropismFlaviviruses such as yellow fever virus (YFV), Zika virus (ZIKV), and dengue virus (DENV) are important human pathogens. A common flavivirus trait is the antagonism of interferon (IFN) signaling to enhance viral replication and spread. We report that like ZIKV NS5 and DENV NS5, YFV NS5 binds human STAT2 (hSTAT2) but not mouse STAT2 (mSTAT2), a type I IFN (IFN-α/β) pathway component. Additionally, we show that contrary to what has been...
Virus-Cell InteractionsTrapping the Enemy: Vermamoeba vermiformis Circumvents Faustovirus Mariensis Dissemination by Enclosing Viral Progeny inside CystsUnderstanding how viruses of microbes interact with its hosts is not only important from a basic scientific point of view but also for a better comprehension of the evolution of life. Studies involving large and giant viruses have revealed original and outstanding mechanisms concerning virus-host relationships. Here, we report a mechanism developed by Vermamoeba vermiformis, a free-living amoeba, to reduce Faustovirus mariensis...
Virus-Cell InteractionsPorcine Reproductive and Respiratory Syndrome Virus Nonstructural Protein 1 Beta Interacts with Nucleoporin 62 To Promote Viral Replication and Immune EvasionPorcine reproductive and respiratory syndrome virus (PRRSV) causes PRRS and is known to effectively suppress host innate immunity. The PRRSV nsp1β protein blocks host mRNA nuclear export, which has been shown to be one of the viral mechanisms for inhibition of antiviral protein production. nsp1β binds to the cellular protein nucleoporin 62 (Nup62), and as a consequence, the nuclear pore complex (NPC) is disintegrated and the...
Virus-Cell InteractionsPolyamine Depletion Inhibits Bunyavirus Infection via Generation of Noninfectious Interfering VirionsBunyaviruses are emerging viral pathogens that cause encephalitis, hemorrhagic fevers, and meningitis. We have uncovered that diverse bunyaviruses require polyamines for productive infection. Polyamines are small, positively charged host-derived molecules that play diverse roles in human cells and in infection. In polyamine-depleted cells, bunyaviruses produce an overabundance of noninfectious particles that are indistinguishable from...
Virus-Cell InteractionsCD4 Expression and Env Conformation Are Critical for HIV-1 Restriction by SERINC5Restriction factors provide the first line of defense against retrovirus infection by posing several blocks to the viral replication cycle. SERINC5 is a novel restriction factor that strongly blocks HIV-1 entry, although it is counteracted by Nef. Currently, it is still unclear how HIV-1 entry is blocked by SERINC5. Notably, this entry block is dependent on viral Env proteins. Laboratory-adapted HIV-1 strains are sensitive, whereas...
Virus-Cell InteractionsK63-Linked Ubiquitin Is Required for Restriction of HIV-1 Reverse Transcription and Capsid Destabilization by Rhesus TRIM5αAlthough the mechanisms by which TRIM5α can induce the abortive disassembly of retroviral capsids have remained obscure, numerous studies have suggested a role for ubiquitination and cellular degradative pathways. These studies have typically relied on global perturbation of cellular degradative pathways. Here, through the use of linkage-specific deubiquitinating enzymes tethered to TRIM5α, we delineate the ubiquitin linkages which...
Virus-Cell InteractionsSam68 Promotes Hepatitis C Virus Replication by Interaction with Stem-Loop 2 of Viral 5′ Untranslated RegionHepatitis C virus (HCV) is a member of the Flaviviridae family, and its infection causes chronic hepatitis, liver cirrhosis, and even hepatocellular carcinoma. No vaccine is available. Many host factors may be implicated in the pathogenesis of HCV-related diseases. This study discloses a new host factor that binds to the HCV 5′ UTR and promotes HCV replication. Sam68 may play an important role in HCV-related diseases, and...
Cellular Response to Infection
Cellular Response to InfectionChandipura Virus Utilizes the Prosurvival Function of RelA NF-κB for Its PropagationRelA/NF-κB participates in a wide spectrum of physiological processes, including shaping immune responses against invading pathogens. In virus-infected cells, RelA typically induces the expression of IFN-β, which restrains viral propagation in neighboring cells involving paracrine mechanisms. Our study suggested that RelA might also play a proviral role. A cell-autonomous RelA activity amplified the yield of Chandipura virus, a...
Cellular Response to Infection | SpotlightTranscriptional Responses of the Trichoplusia ni Midgut to Oral Infection by the Baculovirus Autographa californica Multiple NucleopolyhedrovirusBaculoviruses are virulent pathogens of a number of important insect pest species. In the host Trichoplusia ni, infection begins in the midgut when infectious virions of the occlusion-derived virus (ODV) phenotype enter and subsequently replicate in cells of the midgut epithelium. A second virion phenotype (budded virus [BV]) is produced there, and BV mediates...
Gene Delivery
Gene Delivery | SpotlightIn Vivo Live Imaging of Oncolytic Mammalian Orthoreovirus Expressing NanoLuc Luciferase in Tumor Xenograft MiceEngineering of recombinant MRV for improved oncolytic activity has not yet been achieved due to difficulty in generating autonomous replicating MRV harboring transgenes. Here, we constructed a reporter MRV that can be used to monitor cancer-selective infection by oncolytic MRV in a mouse model. Among the numerous oncolytic viruses, MRV has an advantage in that the wild-type virus shows marked oncolytic activity in patients without any...
Vaccines and Antiviral Agents
Vaccines and Antiviral AgentsRIG-I Activation by a Designer Short RNA Ligand Protects Human Immune Cells against Dengue Virus Infection without Causing CytotoxicityShort hairpin RNA ligands that activate RIG-I induce antiviral responses in infected cells and prevent or control viral infections. Here, we characterized a new short hairpin RNA molecule with high efficacy in antiviral gene activation and showed that this molecule is able to control dengue virus infection. We demonstrate how structural modifications of minimal RNA ligands can lead to increased potency and a wider window of RIG-I-...
Vaccines and Antiviral AgentsHuman Monoclonal Antibodies Potently Neutralize Zika Virus and Select for Escape Mutations on the Lateral Ridge of the Envelope ProteinZika virus (ZIKV) is a global health threat causing severe disease in humans, including microcephaly in newborns and Guillain-Barré syndrome in adults. Here, we analyzed the human monoclonal antibody response to acute ZIKV infection and found that neutralizing antibodies could not elicit Fc-mediated immune effector functions but could potentiate antibody-dependent enhancement of disease. We further identified critical epitopes involved...
Vaccines and Antiviral AgentseCD4-Ig Limits HIV-1 Escape More Effectively than CD4-Ig or a Broadly Neutralizing AntibodyHIV-1 broadly neutralizing antibodies (bNAbs) and engineered antibody-like inhibitors have been compared for their breadths, potencies, and in vivo half-lives. However, a key limitation in the use of antibodies to treat an established HIV-1 infection is the rapid emergence of fully resistant viruses. Entry inhibitors of similar breadths and potencies can differ in the ease with which viral escape variants arise. Here we show...
Vaccines and Antiviral AgentsOptimized Mucosal Modified Vaccinia Virus Ankara Prime/Soluble gp120 Boost HIV Vaccination Regimen Induces Antibody Responses Similar to Those of an Intramuscular RegimenMucosal vaccination is proposed as a method of immunization able to induce protection against mucosal pathogens that is superior to protection provided by parenteral immunization. However, mucosal vaccination often induces serum antigen-specific immune responses of lower magnitude than those induced by parenteral immunization, making the comparison of mucosal and parenteral immunization difficult. We identified vaccine parameters that...
Pathogenesis and Immunity
Pathogenesis and ImmunityGenome-Wide Approach to the CD4 T-Cell Response to Human Herpesvirus 6BHuman herpesvirus 6 is highly prevalent and maintains chronic infection in immunocompetent individuals, with the potential to replicate widely in settings of immunosuppression, leading to clinical disease. Antiviral compounds may be ineffective and/or pose dose-limiting toxicity, and therefore, immune-based therapies have garnered increased interest in recent years. Attempts at addressing this unmet medical need begin with understanding...
Pathogenesis and Immunity | SpotlightExpansion of Stem Cell-Like CD4+ Memory T Cells during Acute HIV-1 Infection Is Linked to Rapid Disease ProgressionUnderstanding the immunopathology of acute HIV-1 infection will help to develop eradication strategies. We demonstrate here that a CD4+ T cell memory subset expands during acute HIV-1 infection, which is associated with disease progression.
Pathogenesis and ImmunityLoss of Fitness of Mexican H7N3 Highly Pathogenic Avian Influenza Virus in Mallards after Circulating in ChickensNot much is known about changes in host adaptation of avian influenza (AI) viruses in birds after long-term circulation in chickens or other terrestrial poultry. Although the origin of AI viruses affecting poultry is wild aquatic birds, the role of these birds in further dispersal of poultry-adapted AI viruses is not clear. Previously, we showed that HPAI viruses isolated early from poultry outbreaks could still infect and transmit well...
Pathogenesis and ImmunityBroadly Neutralizing Antibodies Targeting New Sites of Vulnerability in Hepatitis C Virus E1E2Worldwide, more than 70 million people are infected with hepatitis C virus (HCV), which is a leading cause of hepatocellular carcinoma and liver transplantation. Despite the development of potent direct acting antivirals (DAAs) for HCV treatment, a vaccine is urgently needed due to the high cost of treatment and the possibility of reinfection after cure. Induction of multiple broadly neutralizing antibodies (bNAbs) that target distinct...
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Journal of Virology® (JVI) explores the nature of viruses, reporting important new discoveries and pointing to new directions in research.
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Dr. Rozanne M. Sandri-Goldin, Editor in Chief