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Table of Contents

March 2019; Volume 93,Issue 6

Spotlight

  • Free
    Articles of Significant Interest in This Issue
    Spotlight
    Articles of Significant Interest in This Issue

Gem

  • Free
    Tetraspanins: Architects of Viral Entry and Exit Platforms
    Gem
    Tetraspanins: Architects of Viral Entry and Exit Platforms

    Host factors render cells susceptible to viral infection. One family of susceptibility factors, the tetraspanin proteins, facilitate enveloped virus entry by promoting virus-cell membrane fusion.

    Michael P. Hantak, Enya Qing, James T. Earnest, Tom Gallagher

Structure and Assembly

  • Solution Structure, Self-Assembly, and Membrane Interactions of the Matrix Protein from Newcastle Disease Virus at Neutral and Acidic pH
    Structure and Assembly
    Solution Structure, Self-Assembly, and Membrane Interactions of the Matrix Protein from Newcastle Disease Virus at Neutral and Acidic pH

    The matrix protein of the Newcastle disease virus (NDV) is one of the most abundant viral proteins that regulates the formation of progeny virions. NDV is an avian pathogen that impacts the economics of bird husbandry due to its resulting morbidity and high mortality rates. Moreover, it belongs to the Avulavirus subfamily of the Paramyxoviridae family of Mononegavirales that include dangerous representatives...

    E. V. Shtykova, M. V. Petoukhov, L. A. Dadinova, N. V. Fedorova, V. Yu Tashkin, T. A. Timofeeva, A. L. Ksenofontov, N. A. Loshkarev, L. A. Baratova, C. M. Jeffries, D. I. Svergun, O. V. Batishchev
  • GII.4 Norovirus Protease Shows pH-Sensitive Proteolysis with a Unique Arg-His Pairing in the Catalytic Site
    Structure and Assembly
    GII.4 Norovirus Protease Shows pH-Sensitive Proteolysis with a Unique Arg-His Pairing in the Catalytic Site

    Human noroviruses (NoVs) cause sporadic and epidemic gastroenteritis worldwide. They are divided into seven genogroups (GI to GVII), with each genogroup further divided into several genotypes. Human NoVs belonging to genogroup II and genotype 4 (GII.4) are the most prevalent. Currently, there are no vaccines or antiviral drugs available for NoV infection. The protease encoded by NoV is considered a valuable target because of its...

    Mariya A. Viskovska, Boyang Zhao, Sreejesh Shanker, Jae-Mun Choi, Lisheng Deng, Yongchen Song, Timothy Palzkill, Liya Hu, Mary K. Estes, B. V. Venkataram Prasad
  • Examination and Reconstruction of Three Ancient Endogenous Parvovirus Capsid Protein Gene Remnants Found in Rodent Genomes
    Structure and Assembly
    Examination and Reconstruction of Three Ancient Endogenous Parvovirus Capsid Protein Gene Remnants Found in Rodent Genomes

    Parvovirus endogenous viral elements (EVEs) that have been incorporated into the genomes of different animals represent remnants of the DNA sequences of ancient viruses that infected the ancestors of those animals millions of years ago, but we know little about their properties or how they differ from currently circulating parvoviruses. By expressing the capsid proteins of different parvovirus EVEs that were found integrated into the...

    Heather M. Callaway, Suriyasri Subramanian, Christian A. Urbina, Karen N. Barnard, Robert A. Dick, Carol M. Bator, Susan L. Hafenstein, Robert J. Gifford, Colin R. Parrish
  • Open Access
    Structural Basis of Nanobodies Targeting the Prototype Norovirus
    Structure and Assembly
    Structural Basis of Nanobodies Targeting the Prototype Norovirus

    The discovery of vulnerable regions on norovirus particles is instrumental in the development of effective inhibitors, particularly for GI noroviruses that are genetically diverse. Analysis of these GI.1-specific Nanobodies has shown that similar to GII norovirus particles, the GI particles have vulnerable regions. The only known cofactor region, the HBGA binding pocket, represents the main target for inhibition. With a combination...

    Kerstin Ruoff, Turgay Kilic, Jessica Devant, Anna Koromyslova, Alessa Ringel, Alexander Hempelmann, Celina Geiss, Juliane Graf, Michelle Haas, Imme Roggenbach, Grant Hansman
  • Baculovirus <em>Per Os</em> Infectivity Factor Complex: Components and Assembly
    Structure and Assembly
    Baculovirus Per Os Infectivity Factor Complex: Components and Assembly

    Entry of baculovirus into host insects is mediated by a per os infectivity factor (PIF) complex on the envelopes of occlusion-derived viruses (ODVs). Knowledge of the composition and structure of the PIF complex is fundamental to understanding its mode of action. By using multiple approaches, we determined the complete list of proteins (nine) in the PIF complex. In contrast to previous knowledge in the field, the core complex...

    Xi Wang, Yu Shang, Cheng Chen, Shurui Liu, Meng Chang, Nan Zhang, Hengrui Hu, Fenghua Zhang, Tao Zhang, Zhiying Wang, Xijia Liu, Zhe Lin, Fei Deng, Hualin Wang, Zhen Zou, Just M. Vlak, Manli Wang, Zhihong Hu

Genome Replication and Regulation of Viral Gene Expression

  • Open Access
    M Segment-Based Minigenomes and Virus-Like Particle Assays as an Approach To Assess the Potential of Tick-Borne <em>Phlebovirus</em> Genome Reassortment
    Genome Replication and Regulation of Viral Gene Expression
    M Segment-Based Minigenomes and Virus-Like Particle Assays as an Approach To Assess the Potential of Tick-Borne Phlebovirus Genome Reassortment

    In recent years, there has been a large expansion in the number of emerging tick-borne viruses that are assigned to the Phlebovirus genus. Bunyaviruses have a tripartite segmented genome, and infection of the same host cell by two closely related bunyaviruses can, in theory, result in eight progeny viruses with different genome segment combinations. We used genome analogues expressing reporter genes to assess the abilities of...

    Veronica V. Rezelj, Timothy J. Mottram, Joseph Hughes, Richard M. Elliott, Alain Kohl, Benjamin Brennan
  • A Minigenome Study of Hazara Nairovirus Genomic Promoters
    Genome Replication and Regulation of Viral Gene Expression
    A Minigenome Study of Hazara Nairovirus Genomic Promoters

    A minigenome system for HAZV, closely related to CCHFV, was used to study its genome replication. HAZV genome ends, like those of other sNSV, such as peribunyaviruses and arenaviruses, are highly complementary and serve as promoters for genome synthesis. These promoters are composed of two elements: the extreme termini of both 3′ and 5′ strands that are initially bound to separate sites on the polymerase surface in a sequence-specific...

    Yusuke Matsumoto, Keisuke Ohta, Daniel Kolakofsky, Machiko Nishio

Genetic Diversity and Evolution

  • Koala and Wombat Gammaherpesviruses Encode the First Known Viral NTPDase Homologs and Are Phylogenetically Divergent from All Known Gammaherpesviruses
    Genetic Diversity and Evolution
    Koala and Wombat Gammaherpesviruses Encode the First Known Viral NTPDase Homologs and Are Phylogenetically Divergent from All Known Gammaherpesviruses

    The genome sequences of the koala and wombat gammaherpesviruses show that the viruses form a distinct branch, indicative of a novel genus within the Gammaherpesvirinae. Their genomes contain several new ORFs, including ORFs encoding a β-galactoside α-2,6-sialyltransferase that is phylogenetically closest to poxvirus and insect homologs and the first reported viral NTPDase. NTPDases are ubiquitously expressed in mammals and are...

    Paola K. Vaz, Carol A. Hartley, Sang-Yong Lee, Fiona M. Sansom, Timothy E. Adams, Kathryn Stalder, Lesley Pearce, George Lovrecz, Glenn F. Browning, Christa E. Müller, Joanne M. Devlin
  • Identification and Characterization of a Poliovirus Capsid Mutant with Enhanced Thermal Stability
    Genetic Diversity and Evolution | Spotlight
    Identification and Characterization of a Poliovirus Capsid Mutant with Enhanced Thermal Stability

    Viruses spread by the fecal-oral route need to maintain viability in the environment to ensure transmission. Previous work indicated that bacteria and bacterial surface polysaccharides can stabilize viral particles and enhance transmission. To explore factors that influence viral particle stability, we isolated a mutant poliovirus that is heat resistant. This mutant virus does not require feces for stability at most temperatures but can...

    Y Nguyen, Palmy R. Jesudhasan, Elizabeth R. Aguilera, Julie K. Pfeiffer
  • Open Access
    Horizontal Transfer of a Retrotransposon from the Rice Planthopper to the Genome of an Insect DNA Virus
    Genetic Diversity and Evolution
    Horizontal Transfer of a Retrotransposon from the Rice Planthopper to the Genome of an Insect DNA Virus

    This study provides an example of the horizontal transfer event from a rice planthopper genome to an IIV-6 genome. A small region of the IIV-6 genome (∼300 nt) is highly homologous to the sequences presented in high copy numbers of three rice planthopper genomes that are related to the SINEs, a class of retroposons. The expression of these planthopper SINE-like sequences was confirmed, and corresponding Piwi-interacting RNA-like small...

    Qiankun Yang, Yan Zhang, Ida Bagus Andika, Zhenfeng Liao, Hideki Kondo, Yanhua Lu, Ye Cheng, Linying Li, Yuqing He, Yujuan He, Yuhua Qi, Zongtao Sun, Yuanhua Wu, Fei Yan, Jianping Chen, Junmin Li
  • High Permissiveness for Genetic Exchanges between Enteroviruses of Species A, including Enterovirus 71, Favors Evolution through Intertypic Recombination in Madagascar
    Genetic Diversity and Evolution
    High Permissiveness for Genetic Exchanges between Enteroviruses of Species A, including Enterovirus 71, Favors Evolution through Intertypic Recombination in Madagascar

    Human enteroviruses of species A (EV-A), including EV-A71, are the leading cause of hand-foot-and-mouth disease (HFMD) and may also cause severe neurological manifestations. We investigated the circulation and molecular evolution of EV-A in Madagascar, focusing particularly on the recently described EV-A71 genogroup F. Eight different types, collected mostly in 2011, were identified, highlighting the local circulation and diversity of...

    Romain Volle, Richter Razafindratsimandresy, Marie-Line Joffret, Maël Bessaud, Sendraharimanana Rabemanantsoa, Seta Andriamamonjy, Jonhson Raharinantoanina, Bruno Blondel, Jean-Michel Heraud, Jean-Luc Bailly, Francis Delpeyroux
  • Comparative Analysis of Gammaherpesvirus Circular RNA Repertoires: Conserved and Unique Viral Circular RNAs
    Genetic Diversity and Evolution | Spotlight
    Comparative Analysis of Gammaherpesvirus Circular RNA Repertoires: Conserved and Unique Viral Circular RNAs

    Infection with oncogenic gammaherpesviruses leads to long-term viral persistence through a dynamic interplay between the virus and the host immune system. Critical for remodeling of the host cell environment after the immune responses are viral noncoding RNAs that modulate host signaling pathways without attracting adaptive immune recognition. Despite the importance of noncoding RNAs in persistent infection, the circRNA class of...

    Nathan A. Ungerleider, Vaibhav Jain, Yiping Wang, Nicholas J. Maness, Robert V. Blair, Xavier Alvarez, Cecily Midkiff, Dennis Kolson, Shanshan Bai, Claire Roberts, Walter N. Moss, Xia Wang, Jacqueline Serfecz, Michael Seddon, Terri Lehman, Tianfang Ma, Yan Dong, Rolf Renne, Scott A. Tibbetts, Erik K. Flemington
  • Host Range and Population Survey of <span class="named-content genus-species" id="named-content-1">Spodoptera frugiperda</span> Rhabdovirus
    Genetic Diversity and Evolution
    Host Range and Population Survey of Spodoptera frugiperda Rhabdovirus

    Insect-derived cell lines are widely used commercially for the production of vaccines and protein-based pharmaceuticals. After decades of safe and beneficial use, it was a surprise to the biotechnology industry to discover an endemic rhabdovirus in Sf9 cells. This discovery was made possible only by the substantial advancements in DNA sequencing technologies. Given the public health concerns associated with many rhabdovirus species,...

    L. Schroeder, T. B. Mar, J. R. Haynes, R. Wang, L. Wempe, M. M. Goodin
  • Endogenous Viral Elements Are Widespread in Arthropod Genomes and Commonly Give Rise to PIWI-Interacting RNAs
    Genetic Diversity and Evolution
    Endogenous Viral Elements Are Widespread in Arthropod Genomes and Commonly Give Rise to PIWI-Interacting RNAs

    Our results greatly expand the knowledge of EVE abundance, diversity, and function in an exceptionally wide range of arthropod species. We found that while previous findings in mosquitoes regarding the potential of EVEs to serve as sources of immunological memory via the piRNA pathway may be generalized to other arthropod species, speculation regarding the antiviral function of EVE-derived piRNAs should take into context the fact that...

    Anneliek M. ter Horst, Jared C. Nigg, Fokke M. Dekker, Bryce W. Falk

Virus-Cell Interactions

  • Evolution of the Envelope Glycoprotein of HIV-1 Clade B toward Higher Infectious Properties over the Course of the Epidemic
    Virus-Cell Interactions
    Evolution of the Envelope Glycoprotein of HIV-1 Clade B toward Higher Infectious Properties over the Course of the Epidemic

    Following primary infection by HIV-1, neutralizing antibodies (NAbs) exert selective pressure on the HIV-1 envelope glycoprotein (Env), driving the evolution of the viral population. Previous studies suggested that, as a consequence, Env has evolved at the HIV species level since the start of the epidemic so as to display greater resistance to NAbs. Here, we investigated whether the antigenic evolution of the HIV-1 Env is associated...

    Mélanie Bouvin-Pley, Maxime Beretta, Alain Moreau, Emmanuelle Roch, Asma Essat, Cécile Goujard, Marie-Laure Chaix, Nathalie Moiré, Loïc Martin, Laurence Meyer, Francis Barin, Martine Braibant
  • Functional and Physical Interaction between the Arf Activator GBF1 and Hepatitis C Virus NS3 Protein
    Virus-Cell Interactions
    Functional and Physical Interaction between the Arf Activator GBF1 and Hepatitis C Virus NS3 Protein

    Single-stranded, positive-sense RNA viruses rely to a significant extent on host factors to achieve the replication of their genome. GBF1 is such a cellular protein that is required for the replication of several RNA viruses, but its mechanism of action during viral infections is not yet defined. In this study, we investigated potential interactions that GBF1 might engage in with proteins of HCV, a GBF1-dependent virus. We found that...

    Nadjet Lebsir, Lucie Goueslain, Rayan Farhat, Nathalie Callens, Jean Dubuisson, Catherine L. Jackson, Yves Rouillé
  • USP15 Participates in Hepatitis C Virus Propagation through Regulation of Viral RNA Translation and Lipid Droplet Formation
    Virus-Cell Interactions
    USP15 Participates in Hepatitis C Virus Propagation through Regulation of Viral RNA Translation and Lipid Droplet Formation

    Although ubiquitination has been shown to play important roles in the HCV life cycle, the roles of deubiquitinating enzymes (DUBs), which cleave ubiquitin chains from their substrates, in HCV propagation have not been investigated. Here, we identified USP15 as a DUB regulating HCV propagation. USP15 showed no interaction with viral proteins and no participation in innate immune responses. Deficiency of USP15 in Huh7 cells resulted in...

    Shinji Kusakabe, Tatsuya Suzuki, Yukari Sugiyama, Saori Haga, Kanako Horike, Makoto Tokunaga, Junki Hirano, He Zhang, David Virya Chen, Hanako Ishiga, Yasumasa Komoda, Chikako Ono, Takasuke Fukuhara, Masahiro Yamamoto, Masahito Ikawa, Takashi Satoh, Shizuo Akira, Tomohisa Tanaka, Kohji Moriishi, Moto Fukai, Akinobu Taketomi, Sachiyo Yoshio, Tatsuya Kanto, Tetsuro Suzuki, Toru Okamoto, Yoshiharu Matsuura
  • PF74 Inhibits HIV-1 Integration by Altering the Composition of the Preintegration Complex
    Virus-Cell Interactions
    PF74 Inhibits HIV-1 Integration by Altering the Composition of the Preintegration Complex

    Antiretroviral therapy (ART) that uses various combinations of small molecule inhibitors has been highly effective in controlling HIV. However, the drugs used in the ART regimen are expensive, cause side effects, and face viral resistance. The HIV-1 CA plays critical roles in the virus life cycle and is an attractive therapeutic target. While currently there is no CA-based therapy, highly potent CA-specific inhibitors are being...

    Muthukumar Balasubramaniam, Jing Zhou, Amma Addai, Phillip Martinez, Jui Pandhare, Christopher Aiken, Chandravanu Dash
  • Identification of Clotrimazole Derivatives as Specific Inhibitors of Arenavirus Fusion
    Virus-Cell Interactions
    Identification of Clotrimazole Derivatives as Specific Inhibitors of Arenavirus Fusion

    Emerging human-pathogenic arenaviruses are causative agents of severe hemorrhagic fevers with high mortality and represent serious public health problems. The current lack of a licensed vaccine and the limited treatment options makes the development of novel antiarenaviral therapeutics an urgent need. Using a recombinant pseudotype platform, we uncovered that clotrimazole drugs, in particular TRAM-34, specifically inhibit cell entry of...

    Giulia Torriani, Evgeniya Trofimenko, Jennifer Mayor, Chiara Fedeli, Hector Moreno, Sébastien Michel, Mathieu Heulot, Nadja Chevalier, Gert Zimmer, Neeta Shrestha, Philippe Plattet, Olivier Engler, Sylvia Rothenberger, Christian Widmann, Stefan Kunz
  • Parvulin 14 and Parvulin 17 Bind to HBx and cccDNA and Upregulate Hepatitis B Virus Replication from cccDNA to Virion in an HBx-Dependent Manner
    Virus-Cell Interactions
    Parvulin 14 and Parvulin 17 Bind to HBx and cccDNA and Upregulate Hepatitis B Virus Replication from cccDNA to Virion in an HBx-Dependent Manner

    The HBx protein plays an essential regulatory role in HBV replication. We found that substrate-binding residues on the human parvulin peptidylprolyl cis/trans isomerase proteins Par14 and Par17 bound to conserved arginine-proline (RP) motifs on HBx in the cytoplasm, nucleus, and mitochondria. The HBx-Par14/Par17 interaction stabilized HBx; promoted its translocation to the nucleus and mitochondria; and stimulated...

    Umar Saeed, Jumi Kim, Zahra Zahid Piracha, Hyeonjoong Kwon, Jaesung Jung, Yong-Joon Chwae, Sun Park, Ho-Joon Shin, Kyongmin Kim
  • Natural Inhibitor of Human Cytomegalovirus in Human Seminal Plasma
    Virus-Cell Interactions
    Natural Inhibitor of Human Cytomegalovirus in Human Seminal Plasma

    The role of semen in sexual transmission of human cytomegalovirus (HCMV) is currently unclear. This is surprising, as HCMV is frequently detected in this body fluid and infection is of high danger for neonates and pregnant women. In this study, we found that seminal plasma (SP) dose dependently inhibited HCMV infection. The infection inhibition was specific for HCMV, as other viruses, such as human immunodeficiency virus type 1 (HIV-1)...

    Sina Lippold, Berenike Braun, Franziska Krüger, Mirja Harms, Janis A. Müller, Rüdiger Groß, Jan Münch, Jens von Einem
  • Glycoprotein K8.1A of Kaposi's Sarcoma-Associated Herpesvirus Is a Critical B Cell Tropism Determinant Independent of Its Heparan Sulfate Binding Activity
    Virus-Cell Interactions
    Glycoprotein K8.1A of Kaposi's Sarcoma-Associated Herpesvirus Is a Critical B Cell Tropism Determinant Independent of Its Heparan Sulfate Binding Activity

    Elucidating the molecular mechanisms by which KSHV infects B lymphocytes is critical for understanding how the virus establishes lifelong persistence in infected people, in whom it can cause life-threatening B cell lymphoproliferative disease. Here, we show that K8.1A, a KSHV-encoded glycoprotein on the surfaces of the virus particles, is critical for infection of B cells. This finding stands in marked contrast to previous studies with...

    Stephen J. Dollery, Rey J. Santiago-Crespo, Deboeeta Chatterjee, Edward A. Berger
  • Open Access
    Interferon-Induced Transmembrane Protein 1 Restricts Replication of Viruses That Enter Cells via the Plasma Membrane
    Virus-Cell Interactions
    Interferon-Induced Transmembrane Protein 1 Restricts Replication of Viruses That Enter Cells via the Plasma Membrane

    Host susceptibility to viral infection is multifactorial, but early control of viruses not previously encountered is predominantly mediated by the interferon-stimulated gene (ISG) family. There are upwards of 300 of these genes, the majority of which do not have a clearly defined function or mechanism of action. The cellular location of these proteins may have an important effect on their function. One ISG located at the plasma membrane...

    S. E. Smith, D. C. Busse, S. Binter, S. Weston, C. Diaz Soria, B. M. Laksono, S. Clare, S. Van Nieuwkoop, B. G. Van den Hoogen, M. Clement, M. Marsden, I. R. Humphreys, M. Marsh, R. L. de Swart, R. S. Wash, J. S. Tregoning, P. Kellam
  • Infectious Entry of Merkel Cell Polyomavirus
    Virus-Cell Interactions | Spotlight
    Infectious Entry of Merkel Cell Polyomavirus

    MCPyV is the first polyomavirus directly implicated in the development of an aggressive human cancer, Merkel cell carcinoma (MCC). Although MCPyV is constantly shed from healthy skin, the MCC incidence increases among aging and immunocompromised individuals. To date, the events connecting initial MCPyV infection and subsequent transformation still remain elusive. MCPyV differs from other known polyomaviruses concerning its cell tropism...

    Miriam Becker, Melissa Dominguez, Lilo Greune, Laura Soria-Martinez, Moritz M. Pfleiderer, Rachel Schowalter, Christopher B. Buck, Bärbel S. Blaum, M. Alexander Schmidt, Mario Schelhaas
  • Open Access
    Flexibility <em>In Vitro</em> of Amino Acid 226 in the Receptor-Binding Site of an H9 Subtype Influenza A Virus and Its Effect <em>In Vivo</em> on Virus Replication, Tropism, and Transmission
    Virus-Cell Interactions
    Flexibility In Vitro of Amino Acid 226 in the Receptor-Binding Site of an H9 Subtype Influenza A Virus and Its Effect In Vivo on Virus Replication, Tropism, and Transmission

    A single amino acid change at position 226 in the hemagglutinin (HA) from glutamine (Q) to leucine (L) has been shown to play a key role in receptor specificity switching in various influenza virus HA subtypes, including H9. We tested the flexibility of amino acid usage and determined the effects of such changes. The results reveal that amino acids other than L226 and Q226 are well tolerated and that some amino acids allow for the...

    Adebimpe O. Obadan, Jefferson Santos, Lucas Ferreri, Andrew J. Thompson, Silvia Carnaccini, Ginger Geiger, Ana S. Gonzalez Reiche, Daniela S. Rajão, James C. Paulson, Daniel R. Perez
  • The Glucocorticoid Receptor (GR) Stimulates Herpes Simplex Virus 1 Productive Infection, in Part Because the Infected Cell Protein 0 (ICP0) Promoter Is Cooperatively Transactivated by the GR and Krüppel-Like Transcription Factor 15
    Virus-Cell Interactions
    The Glucocorticoid Receptor (GR) Stimulates Herpes Simplex Virus 1 Productive Infection, in Part Because the Infected Cell Protein 0 (ICP0) Promoter Is Cooperatively Transactivated by the GR and Krüppel-Like Transcription Factor 15

    The ability of herpes simplex virus 1 (HSV-1) to periodically reactivate from latency results in virus transmission and recurrent disease. The incidence of reactivation from latency is increased by chronic or acute stress. Stress increases the levels of corticosteroids, which bind and activate the glucocorticoid receptor (GR). Since GR activation is an immediate early response to stress, we tested whether the GR influences productive...

    Jeffery B. Ostler, Kelly S. Harrison, Kayla Schroeder, Prasanth Thunuguntla, Clinton Jones
  • Rhesus Macaque Rhadinovirus Encodes a Viral Interferon Regulatory Factor To Disrupt Promyelocytic Leukemia Nuclear Bodies and Antagonize Type I Interferon Signaling
    Virus-Cell Interactions
    Rhesus Macaque Rhadinovirus Encodes a Viral Interferon Regulatory Factor To Disrupt Promyelocytic Leukemia Nuclear Bodies and Antagonize Type I Interferon Signaling

    KSHV and RRV encode a unique set of homologs of cellular IFN regulatory factors, termed vIRFs, which are hypothesized to help these viruses evade the innate immune response and establish infections in their respective hosts. Our work elucidates the role of one RRV vIRF, R12, and demonstrates that RRV can dampen the type I IFN response downstream of IFN signaling, which would be important for establishing a successful infection in...

    Laura K. Springgay, Kristin Fitzpatrick, Byung Park, Ryan D. Estep, Scott W. Wong
  • US3 Kinase-Mediated Phosphorylation of Tegument Protein VP8 Plays a Critical Role in the Cellular Localization of VP8 and Its Effect on the Lipid Metabolism of Bovine Herpesvirus 1-Infected Cells
    Virus-Cell Interactions
    US3 Kinase-Mediated Phosphorylation of Tegument Protein VP8 Plays a Critical Role in the Cellular Localization of VP8 and Its Effect on the Lipid Metabolism of Bovine Herpesvirus 1-Infected Cells

    Nuclear localization signals (NLSs) and nuclear export signals (NESs) are important elements directing VP8 to the desired locations in the BoHV-1-infected cell. In this study, a critical regulator that switches the nuclear and cytoplasmic localization of VP8 in BoHV-1-infected cells was identified. BoHV-1 used viral kinase US3 to regulate the cellular localization of VP8. Early during BoHV-1 infection VP8 was localized in the nucleus,...

    Kuan Zhang, Tara Donovan, Soumya Sucharita, Robert Brownlie, Marlene Snider, Suresh K. Tikoo, Sylvia van Drunen Littel-van den Hurk
  • Kaposi’s Sarcoma-Associated Herpesvirus LANA-Adjacent Regions with Distinct Functions in Episome Segregation or Maintenance
    Virus-Cell Interactions
    Kaposi’s Sarcoma-Associated Herpesvirus LANA-Adjacent Regions with Distinct Functions in Episome Segregation or Maintenance

    KSHV LANA mediates episomal persistence of viral genomes. LANA binds the KSHV terminal-repeat (TR) sequence to mediate DNA replication and tethers KSHV DNA to mitotic chromosomes to segregate genomes to daughter cell nuclei. Here, we investigate LANA sequence upstream of the internal repeat elements that contributes to episome segregation and persistence. Mutants with deletions within this sequence maintained the ability to bind mitotic...

    Franceline Juillard, Erika De León Vázquez, Min Tan, Shijun Li, Kenneth M. Kaye
  • RNA-Binding Motif Protein 24 (RBM24) Is Involved in Pregenomic RNA Packaging by Mediating Interaction between Hepatitis B Virus Polymerase and the Epsilon Element
    Virus-Cell Interactions
    RNA-Binding Motif Protein 24 (RBM24) Is Involved in Pregenomic RNA Packaging by Mediating Interaction between Hepatitis B Virus Polymerase and the Epsilon Element

    Hepatitis B virus (HBV) is a ubiquitous human pathogen, and HBV infection is a major global health burden. Chronic HBV infection is associated with the development of liver diseases, including fulminant hepatitis, hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. A currently approved vaccine can prevent HBV infection, and medications are able to reduce viral loads and prevent liver disease progression. However, current...

    Yongxuan Yao, Bo Yang, Yingshan Chen, Hui Wang, Xue Hu, Yuan Zhou, Xiuzhu Gao, Mengji Lu, Junqi Niu, Zhe Wen, Chunchen Wu, Xinwen Chen
  • Peroxiredoxin 1, a Novel HBx-Interacting Protein, Interacts with Exosome Component 5 and Negatively Regulates Hepatitis B Virus (HBV) Propagation through Degradation of HBV RNA
    Virus-Cell Interactions
    Peroxiredoxin 1, a Novel HBx-Interacting Protein, Interacts with Exosome Component 5 and Negatively Regulates Hepatitis B Virus (HBV) Propagation through Degradation of HBV RNA

    Hepatitis B virus (HBV) infection is a major global health problem. HBx plays important roles in HBV replication and viral carcinogenesis through its interaction with host factors. In this study, we identified Prdx1 as a novel HBx-binding protein. We provide evidence suggesting that Prdx1 promotes HBV RNA decay through interaction with HBV RNA and Exosc5, leading to downregulation of HBV RNA. These results suggest that Prdx1 negatively...

    Lin Deng, Xiang Gan, Masahiko Ito, Ming Chen, Hussein H. Aly, Chieko Matsui, Takayuki Abe, Koichi Watashi, Takaji Wakita, Tetsuro Suzuki, Toru Okamoto, Yoshiharu Matsuura, Masashi Mizokami, Ikuo Shoji, Hak Hotta
  • Lund Human Mesencephalic (LUHMES) Neuronal Cell Line Supports Herpes Simplex Virus 1 Latency <em>In Vitro</em>
    Virus-Cell Interactions
    Lund Human Mesencephalic (LUHMES) Neuronal Cell Line Supports Herpes Simplex Virus 1 Latency In Vitro

    Herpes simplex virus (HSV) is responsible for significant morbidity in humans due to its ability to cause oral and genital lesions, ocular disease, and encephalitis. While antivirals can attenuate the severity and frequency of disease, there is no vaccine or cure. Understanding the molecular details of HSV latency and reactivation is key to the development of new therapies. One of the difficulties in studying HSV latency has been the...

    Terri G. Edwards, David C. Bloom
  • Porcine Circovirus 2 Uses a Multitude of Weak Binding Sites To Interact with Heparan Sulfate, and the Interactions Do Not Follow the Symmetry of the Capsid
    Virus-Cell Interactions
    Porcine Circovirus 2 Uses a Multitude of Weak Binding Sites To Interact with Heparan Sulfate, and the Interactions Do Not Follow the Symmetry of the Capsid

    It has been demonstrated that porcine circovirus 2 (PCV2) attaches to cells via heparan sulfate (HS) and chondroitin sulfate B (CSB) glycosaminoglycans; however, the underlying structural mechanism describing the HS/CSB recognition by PCV2 remains to be explored. We used cryo-electron microscopy with single-particle analysis, symmetry expansion, and focused classification to visualize the interaction between the PCV2 capsid and heparin...

    Sonali Dhindwal, Bryant Avila, Shanshan Feng, Reza Khayat

Cellular Response to Infection

  • Investigation of Host Range of and Host Defense against a Mitochondrially Replicating Mitovirus
    Cellular Response to Infection | Spotlight
    Investigation of Host Range of and Host Defense against a Mitochondrially Replicating Mitovirus

    Capsidless mitoviruses, which are ubiquitously detected in filamentous fungi, have the simplest RNA genomes of 2.2 to 4.4 kb, encoding only RNA-dependent RNA polymerase. Despite their simple genomes, detailed biological characterization of mitoviruses has been hampered by their mitochondrial location within the cell, posing challenges to their experimental introduction and study. Here we developed a protoplast fusion-based protocol for...

    Sabitree Shahi, Ana Eusebio-Cope, Hideki Kondo, Bradley I. Hillman, Nobuhiro Suzuki
  • West Nile Virus-Inclusive Single-Cell RNA Sequencing Reveals Heterogeneity in the Type I Interferon Response within Single Cells
    Cellular Response to Infection
    West Nile Virus-Inclusive Single-Cell RNA Sequencing Reveals Heterogeneity in the Type I Interferon Response within Single Cells

    West Nile virus (WNV) is a clinically relevant pathogen responsible for recurrent epidemics of neuroinvasive disease. Type I interferon is essential for promoting an antiviral response against WNV infection; however, it is unclear how heterogeneity in the antiviral response at the single-cell level impacts viral control. Specifically, conventional approaches lack the ability to distinguish differences across cells with varying viral...

    Justin T. O’Neal, Amit A. Upadhyay, Amber Wolabaugh, Nirav B. Patel, Steven E. Bosinger, Mehul S. Suthar
  • Open Access
    The Human CD4<sup>+</sup> T Cell Response against Mumps Virus Targets a Broadly Recognized Nucleoprotein Epitope
    Cellular Response to Infection
    The Human CD4+ T Cell Response against Mumps Virus Targets a Broadly Recognized Nucleoprotein Epitope

    Recent outbreaks of mumps among vaccinated young adults have been reported worldwide. Humoral responses against mumps virus (MuV) are well characterized, although no correlate of protection has been elucidated, stressing the need to better understand cellular MuV-specific immunity. In this study, we identified the first MuV T cell epitope, which is derived from the viral nucleoprotein (MuV-N) and was recognized by a cytotoxic/Th1 CD4...

    Jelle de Wit, Maarten E. Emmelot, Martien C. M. Poelen, Josien Lanfermeijer, Wanda G. H. Han, Cécile A. C. M. van Els, Patricia Kaaijk
  • Unique Transcriptional Architecture in Airway Epithelial Cells and Macrophages Shapes Distinct Responses following Influenza Virus Infection <em>Ex Vivo</em>
    Cellular Response to Infection | Spotlight
    Unique Transcriptional Architecture in Airway Epithelial Cells and Macrophages Shapes Distinct Responses following Influenza Virus Infection Ex Vivo

    Airway epithelial cells (AEC) and airway macrophages (AM) represent major targets of influenza A virus (IAV) infection in the lung, yet the two cell types respond very differently to IAV infection. We have used RNA sequencing to define the host transcriptional responses in each cell type under steady-state conditions as well as following IAV infection. To do this, different cell subsets isolated from the lungs of mock- and IAV-infected...

    Joel Z. Ma, Wy Ching Ng, Luke Zappia, Linden J. Gearing, Moshe Olshansky, Kym Pham, Karey Cheong, Arthur Hsu, Stephen J. Turner, Odilia Wijburg, Sarah L. Londrigan, Andrew G. Brooks, Patrick C. Reading

Vaccines and Antiviral Agents

  • Open Access
    Why Are CD8 T Cell Epitopes of Human Influenza A Virus Conserved?
    Vaccines and Antiviral Agents
    Why Are CD8 T Cell Epitopes of Human Influenza A Virus Conserved?

    Universal influenza vaccines against the conserved epitopes of influenza A virus have been proposed to minimize the burden of seasonal outbreaks and prepare for the pandemics. However, it is not clear how rapidly T cell-inducing vaccines will select for viruses that escape these T cell responses. Our mathematical models explore the factors that contribute to the conservation of CD8 T cell epitopes and how rapidly the virus will evolve...

    Zheng-Rong Tiger Li, Veronika I. Zarnitsyna, Anice C. Lowen, Daniel Weissman, Katia Koelle, Jacob E. Kohlmeier, Rustom Antia
  • Broadly Cross-Reactive, Nonneutralizing Antibodies against Influenza B Virus Hemagglutinin Demonstrate Effector Function-Dependent Protection against Lethal Viral Challenge in Mice
    Vaccines and Antiviral Agents
    Broadly Cross-Reactive, Nonneutralizing Antibodies against Influenza B Virus Hemagglutinin Demonstrate Effector Function-Dependent Protection against Lethal Viral Challenge in Mice

    While broadly protective antibodies against the influenza A virus hemagglutinin have been well studied, very limited information is available for antibodies that broadly recognize influenza B viruses. Similarly, the development of a universal or broadly protective influenza B virus vaccine lags behind the development of such a vaccine for influenza A virus. More information about epitope location and mechanism of action of broadly...

    Guha Asthagiri Arunkumar, Andriani Ioannou, Teddy John Wohlbold, Philip Meade, Sadaf Aslam, Fatima Amanat, Juan Ayllon, Adolfo García-Sastre, Florian Krammer
  • Viral Replicative Capacity, Antigen Availability via Hematogenous Spread, and High T<sub>FH</sub>:T<sub>FR</sub> Ratios Drive Induction of Potent Neutralizing Antibody Responses
    Vaccines and Antiviral Agents
    Viral Replicative Capacity, Antigen Availability via Hematogenous Spread, and High TFH:TFR Ratios Drive Induction of Potent Neutralizing Antibody Responses

    Neutralizing antibody response is the best-known correlate of long-term protective immunity for most of the currently licensed clinically effective viral vaccines. However, the host immune and viral factors that are critical for the induction of robust and durable antiviral humoral immune responses are not well understood. Our study provides insight into the dynamics of key cellular mediators of germinal center reaction during live...

    Preethi Eldi, Geeta Chaudhri, Stephen L. Nutt, Timothy P. Newsome, Gunasegaran Karupiah
  • <em>In Vitro</em> and <em>In Vivo</em> Characterization of Novel Neuraminidase Substitutions in Influenza A(H1N1)pdm09 Virus Identified Using Laninamivir-Mediated <em>In Vitro</em> Selection
    Vaccines and Antiviral Agents
    In Vitro and In Vivo Characterization of Novel Neuraminidase Substitutions in Influenza A(H1N1)pdm09 Virus Identified Using Laninamivir-Mediated In Vitro Selection

    With the widespread emergence of NAI-resistant influenza virus strains, continuous monitoring of mutations that confer antiviral resistance is needed. Laninamivir is the most recently approved NAI in several countries; few data exist related to the in vitro selection of viral mutations conferring resistance to laninamivir. Thus, we screened and identified substitutions conferring resistance to laninamivir by random mutagenesis...

    Khristine Kaith S. Lloren, Jin Jung Kwon, Won-Suk Choi, Ju Hwan Jeong, Su Jeong Ahn, Young Ki Choi, Yun Hee Baek, Min-Suk Song
  • A Recombinant Rabies Virus Expressing the Marburg Virus Glycoprotein Is Dependent upon Antibody-Mediated Cellular Cytotoxicity for Protection against Marburg Virus Disease in a Murine Model
    Vaccines and Antiviral Agents
    A Recombinant Rabies Virus Expressing the Marburg Virus Glycoprotein Is Dependent upon Antibody-Mediated Cellular Cytotoxicity for Protection against Marburg Virus Disease in a Murine Model

    Marburg virus (MARV) is a virus similar to Ebola virus and also causes a hemorrhagic disease which is highly lethal. In contrast to EBOV, only a few vaccines have been developed against MARV, and researchers do not understand what kind of immune responses are required to protect from MARV. Here we show that antibodies directed against MARV after application of our vaccine protect in an animal system but fail to neutralize the virus in a...

    Rohan Keshwara, Katie R. Hagen, Tiago Abreu-Mota, Amy B. Papaneri, David Liu, Christoph Wirblich, Reed F. Johnson, Matthias J. Schnell
  • Resistance to Second-Generation HIV-1 Maturation Inhibitors
    Vaccines and Antiviral Agents
    Resistance to Second-Generation HIV-1 Maturation Inhibitors

    HIV-1 maturation inhibitors are a class of small-molecule compounds that block a late step in the viral protease-mediated processing of the Gag polyprotein precursor, the viral protein responsible for the formation of virus particles. The first-in-class HIV-1 maturation inhibitor bevirimat was highly effective in blocking HIV-1 replication, but its activity was compromised by naturally occurring sequence polymorphisms within Gag....

    Emiko Urano, Uddhav Timilsina, Justin A. Kaplan, Sherimay Ablan, Dibya Ghimire, Phuong Pham, Nishani Kuruppu, Rebecca Mandt, Stewart R. Durell, Theodore J. Nitz, David E. Martin, Carl T. Wild, Ritu Gaur, Eric O. Freed

Pathogenesis and Immunity

  • Geminiviral V2 Protein Suppresses Transcriptional Gene Silencing through Interaction with AGO4
    Pathogenesis and Immunity
    Geminiviral V2 Protein Suppresses Transcriptional Gene Silencing through Interaction with AGO4

    In plants, the RNA-directed DNA methylation (RdDM) pathway is a natural antiviral defense mechanism against geminiviruses. However, how geminiviruses counter RdDM-mediated defense is largely unknown. Our findings reveal that Cotton leaf curl Multan virus V2 contributes to viral infection by interaction with NbAGO4 to suppress RNA-directed DNA methylation-mediated transcriptional gene silencing in plants. Our work provides the...

    Yunjing Wang, Yuyao Wu, Qian Gong, Asigul Ismayil, Yuxiang Yuan, Bi Lian, Qi Jia, Meng Han, Haiteng Deng, Yiguo Hong, Linda Hanley-Bowdoin, Yijun Qi, Yule Liu
  • Open Access
    Positive Selection at Key Residues in the HIV Envelope Distinguishes Broad and Strain-Specific Plasma Neutralizing Antibodies
    Pathogenesis and Immunity
    Positive Selection at Key Residues in the HIV Envelope Distinguishes Broad and Strain-Specific Plasma Neutralizing Antibodies

    Millions of people are still being infected with HIV decades after the first recognition of the virus. Currently, no vaccine is able to elicit bNAbs that will prevent infection by global HIV strains. Several studies have implicated HIV Env diversity in the development of breadth. However, Env evolution in individuals who fail to develop breadth despite mounting potent strain-specific neutralizing responses has not been well defined....

    Batsirai M. Mabvakure, Cathrine Scheepers, Nigel Garrett, Salim Abdool Karim, Carolyn Williamson, Lynn Morris, Penny L. Moore
  • TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection
    Pathogenesis and Immunity
    TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection

    Broad-spectrum antiviral drugs against highly pathogenic coronaviruses and other emerging viruses are desirable to enable a rapid response to pandemic threats. Transmembrane protease serine type 2 (TMPRSS2), a protease belonging to the type II transmembrane serine protease family, cleaves the coronavirus spike protein, making it a potential therapeutic target for coronavirus infections. Here, we examined the role of TMPRSS2 using animal...

    Naoko Iwata-Yoshikawa, Tadashi Okamura, Yukiko Shimizu, Hideki Hasegawa, Makoto Takeda, Noriyo Nagata
  • Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus
    Pathogenesis and Immunity
    Acute Respiratory Infection in Human Dipeptidyl Peptidase 4-Transgenic Mice Infected with Middle East Respiratory Syndrome Coronavirus

    Middle East respiratory syndrome coronavirus (MERS-CoV) infections are endemic in the Middle East and a threat to public health worldwide. Rodents are not susceptible to the virus because they do not express functional receptors; therefore, we generated a new animal model of MERS-CoV infection based on transgenic mice expressing human DPP4 (hDPP4). The pattern of hDPP4 expression in this model was similar to that in human tissues (...

    Naoko Iwata-Yoshikawa, Tadashi Okamura, Yukiko Shimizu, Osamu Kotani, Hironori Sato, Hanako Sekimukai, Shuetsu Fukushi, Tadaki Suzuki, Yuko Sato, Makoto Takeda, Masato Tashiro, Hideki Hasegawa, Noriyo Nagata
  • HIV Subtype and Nef-Mediated Immune Evasion Function Correlate with Viral Reservoir Size in Early-Treated Individuals
    Pathogenesis and Immunity
    HIV Subtype and Nef-Mediated Immune Evasion Function Correlate with Viral Reservoir Size in Early-Treated Individuals

    While combination antiretroviral therapies (cART) have transformed HIV infection into a chronic manageable condition, they do not act upon the latent HIV reservoir and are therefore not curative. As HIV cure or remission should be more readily achievable in individuals with smaller HIV reservoirs, achieving a deeper understanding of the clinical, immunological, and virological determinants of reservoir size is critical to eradication...

    Fredrick H. Omondi, Sandali Chandrarathna, Shariq Mujib, Chanson J. Brumme, Steven W. Jin, Hanwei Sudderuddin, Rachel L. Miller, Asa Rahimi, Oliver Laeyendecker, Phil Bonner, Feng Yun Yue, Erika Benko, Colin M. Kovacs, Mark A. Brockman, Mario Ostrowski, Zabrina L. Brumme
  • Establishment of a Novel Humanized Mouse Model To Investigate <em>In Vivo</em> Activation and Depletion of Patient-Derived HIV Latent Reservoirs
    Pathogenesis and Immunity
    Establishment of a Novel Humanized Mouse Model To Investigate In Vivo Activation and Depletion of Patient-Derived HIV Latent Reservoirs

    Sustained remission of HIV infection is prevented by a persistent reservoir of latently infected cells capable of reinitiating systemic infection and viremia. To evaluate strategies to reactivate and deplete this reservoir, we developed and characterized a new humanized mouse model consisting of highly immunodeficient mice intrasplenically injected with peripheral blood mononuclear cells from long-term ART-suppressed HIV-infected donors...

    Nina C. Flerin, Ariola Bardhi, Jian Hua Zheng, Maria Korom, Joy Folkvord, Colin Kovacs, Erika Benko, Ronald Truong, Talia Mota, Elizabeth Connick, R. Brad Jones, Rebecca M. Lynch, Harris Goldstein
  • Inhibition of Ongoing Influenza A Virus Replication Reveals Different Mechanisms of RIG-I Activation
    Pathogenesis and Immunity
    Inhibition of Ongoing Influenza A Virus Replication Reveals Different Mechanisms of RIG-I Activation

    The induction of an IFN response by IAV is mainly mediated by the RNA sensor RIG-I. The physiological RIG-I ligands produced during IAV infection are not fully elucidated. Cellular constraints leading to the inhibition of ongoing viral replication likely potentiate an erroneous viral polymerase producing aberrant viral RNA species activating RIG-I. Here, we demonstrate that RIG-I activation during chemical inhibition of continuous viral...

    GuanQun Liu, Yao Lu, Qiang Liu, Yan Zhou
  • LXR Alpha Restricts Gammaherpesvirus Reactivation from Latently Infected Peritoneal Cells
    Pathogenesis and Immunity
    LXR Alpha Restricts Gammaherpesvirus Reactivation from Latently Infected Peritoneal Cells

    Liver X receptors (LXRs) are nuclear receptors that mediate cholesterol and fatty acid homeostasis. Importantly, as ligand-activated transcription factors, LXRs represent potential targets for the treatment of hypercholesterolemia and atherosclerosis. Here, we demonstrate that LXRα, one of the two LXR isoforms, restricts reactivation of latent gammaherpesvirus from peritoneal cells. As gammaherpesviruses are ubiquitous oncogenic agents...

    P. T. Lange, C. N. Jondle, E. J. Darrah, K. E. Johnson, V. L. Tarakanova
  • The Virulence of Different Vaccinia Virus Strains Is Directly Proportional to Their Ability To Downmodulate Specific Cell-Mediated Immune Compartments <em>In Vivo</em>
    Pathogenesis and Immunity
    The Virulence of Different Vaccinia Virus Strains Is Directly Proportional to Their Ability To Downmodulate Specific Cell-Mediated Immune Compartments In Vivo

    Vaccinia virus was used as vaccine against smallpox and was instrumental in the successful eradication of that disease. Although smallpox vaccination is no longer in place in the overall population, the use of vaccinia virus in the development of viral vector-based vaccines has become popular. Nonetheless, different vaccinia virus strains are known and induce different immune responses. To look into this, we compared immune responses...

    Lorena F. D. de Freitas, Rafael P. Oliveira, Mariana C. G. Miranda, Raíssa P. Rocha, Edel F. Barbosa-Stancioli, Ana Maria C. Faria, Flávio G. da Fonseca

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Journal of Virology: 93 (6)

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volume 93, issue 6
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  • Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus
  • COVID-19 Vaccines: “Warp Speed” Needs Mind Melds, Not Warped Minds
  • Nucleocapsid Protein Recruitment to Replication-Transcription Complexes Plays a Crucial Role in Coronaviral Life Cycle
  • Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry
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