Characterization of murine antibody responses to vaccinia virus envelope protein A14 reveals an immunodominant antigen lacking of effective neutralization targets Virology (IF 3.353) Pub Date : 2018-03-17 Xiangzhi Meng, Thomas Kaever, Bo Yan, Paula Traktman, Dirk M. Zajonc, Bjoern Peters, Shane Crotty, Yan Xiang
NDV entry into dendritic cells through macropinocytosis and suppression of T lymphocyte proliferation Virology (IF 3.353) Pub Date : 2018-03-15 Lei Tan, Yuqiang Zhang, Changtao Qiao, Yanmei Yuan, Yingjie Sun, Xusheng Qiu, Chunchun Meng, Cuiping Song, Ying Liao, Muhammad Munir, Venugopal Nair, Zhuang Ding, Xiufan Liu, Chan Ding
Newcastle disease virus (NDV) causes major economic losses in the poultry industry. Previous studies have shown that NDV utilizes different pathways to infect various cells, including dendritic cells (DCs). Here, we demonstrate that NDV gains entry into DCs mainly via macropinocytosis and clathrin-mediated endocytosis. The detection of cytokines interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), interleukin-4 (IL-4) and interleukin-10 (IL-10) indicates that NDV significantly induces Th1 responses and lowers Th2 responses. Furthermore, NDV entry into DCs resulted in the upregulation of TNF-related apoptosis-inducing ligand (TRAIL) and cleaved caspase-3 proteins, which in turn activated the extrinsic apoptosis pathway and induced DCs apoptosis. Transwell® co-culture demonstrated that direct contact between live NDV-stimulated DCs and T cells, rather than heated-inactivated NDV, inhibited CD4+ T cell proliferation. Taken together, these findings provide new insights into the mechanism underlying NDV infections, particularly in relation to antigen presentation cells and suppression of T cell proliferation.
Systemic antibodies administered by passive immunization prevent generalization of the infection by foot-and-mouth disease virus in cattle after oronasal challenge Virology (IF 3.353) Pub Date : 2018-03-15 Florencia Barrionuevo, Sebastián Di Giacomo, Danilo Bucafusco, Andrea Ayude, Juan Schammas, M. Cruz Miraglia, Alejandra Capozzo, Manuel V. Borca, Mariano Perez-Filgueira
The role of passively transferred sera in the protection against aerogenous foot-and-mouth disease (FMD) virus infection in cattle was evaluated using vaccine-induced immune serum preparations obtained at 7 and 26 days post-vaccination (dpv). We showed that circulating antibodies were sufficient to prevent disease generalization after oronasal infection in animals passively transferred with 26-dpv serum but not with the 7-dpv serum. Conversely, conventional FMD vaccination provided clinical protection at 7 dpv, promoting fast and robust antibody responses upon challenge and even though antibody titers were similar to those found in animals passively immunized with 7-dpv serum. These results demonstrate that presence of antigen-specific antibodies is critical to prevent the dissemination of the virus within the animal. Conventional FMD vaccination additionally promoted the deployment of rapid, high titer and isotype-switched antibody responses at systemic and mucosal levels after infection, thus conferring protection even in the presence of low pre-challenge antibody titers.
Octapartite negative-sense RNA genome of High Plains wheat mosaic virus encodes two suppressors of RNA silencing Virology (IF 3.353) Pub Date : 2018-03-15 Adarsh K. Gupta, Gary L. Hein, Robert A. Graybosch, Satyanarayana Tatineni
High Plains wheat mosaic virus (HPWMoV, genus Emaravirus; family Fimoviridae), transmitted by the wheat curl mite (Aceria tosichella Keifer), harbors a monocistronic octapartite single-stranded negative-sense RNA genome. In this study, putative proteins encoded by HPWMoV genomic RNAs 2–8 were screened for potential RNA silencing suppression activity by using a green fluorescent protein-based reporter agroinfiltration assay. We found that proteins encoded by RNAs 7 (P7) and 8 (P8) suppressed silencing induced by single- or double-stranded RNAs and efficiently suppressed the transitive pathway of RNA silencing. Additionally, a Wheat streak mosaic virus (WSMV, genus Tritimovirus; family Potyviridae) mutant lacking the suppressor of RNA silencing (ΔP1) but having either P7 or P8 from HPWMoV restored cell-to-cell and long-distance movement in wheat, thus indicating that P7 or P8 rescued silencing suppressor-deficient WSMV. Furthermore, HPWMoV P7 and P8 substantially enhanced the pathogenicity of Potato virus X in Nicotiana benthamiana. Collectively, these data demonstrate that the octapartite genome of HPWMoV encodes two suppressors of RNA silencing.
Networks of protein-protein interactions among structural proteins of budded virus of Bombyx mori nucleopolyhedrovirus Virology (IF 3.353) Pub Date : 2018-03-15 Jianjia Zhang, Min Feng, Ying Fan, Weifan Xu, Qin Zheng, Xiaofeng Wu
The structural proteins of baculovirus are well studied, but the interactions between them remain unclear. In order to reveal protein-protein interactions among viral structural proteins and their associated proteins of the budded virus of Bombyx mori nucleopolyhedrovirus (BmNPV), the yeast two hybrid (Y2H) system was used to evaluate the interactions of 27 viral genes products. Fifty-seven interactions were identified with 51 binary interactions and 6 self-associations. Among them, 10 interactions were further confirmed by co-immunoprecipitation assays. Five interaction networks were formed based on the direct-cross Y2H assays. VP39, 38 K, and FP were identified to interact with most of the viral proteins, and may form major structural elements of the viral architecture. In addition, each envelope protein was detected to interact with more than one capsid protein. These results suggest how viral structural and structural associated proteins may assemble to form a complete virus through interacting with each other.
Porcine reproductive and respiratory syndrome virus induces HMGB1 secretion via activating PKC-delta to trigger inflammatory response Virology (IF 3.353) Pub Date : 2018-03-15 Rong Wang, Liping Yang, Yali Zhang, Junyan Li, Liran Xu, Yueqiang Xiao, Qian Zhang, Liang Bai, Sihai Zhao, Enqi Liu, Yan-Jin Zhang
Porcine reproductive and respiratory syndrome virus (PRRSV) causes inflammatory injuries in infected pigs. PRRSV induces secretion of high mobility group box 1 (HMGB1) that enhances inflammatory response. However, the mechanism of PRRSV-induced HMGB1 secretion is unknown. Here, we discovered PRRSV induced HMGB1 secretion via activating protein kinase C-delta (PKCδ). HMGB1 secretion was positively correlated with PKCδ activation in PRRSV-infected cells in a dose and time-dependent manner. Suppression of PKCδ with inhibitor and siRNA significantly blocked PRRSV-induced HMGB1 translocation and secretion, which indicates PKCδ activation is essential for the PRRSV-mediated HMGB1 secretion. In addition, PKCδ knockdown in PRRSV-infected cells led to downregulation of inflammatory cytokines, including IL-1beta and IL-6. Moreover, PRRSV E and pORF5a proteins were found to activate PKCδ and consequent HMGB1 secretion. These results demonstrate PRRSV activates PKCδ to induce HMGB1 secretion via E and pORF5a. This finding provides insights on the inflammatory response and pathogenesis of PRRSV infection.
Differential phosphorylation and n-terminal configuration of capsid subunits in parvovirus assembly and viral trafficking Virology (IF 3.353) Pub Date : 2018-03-15 Jon Gil-Ranedo, Eva Hernando, Noelia Valle, Laura Riolobos, Beatriz Maroto, José M. Almendral
The T1 parvovirus Minute Virus of Mice (MVM) was used to study the roles that phosphorylation and N-terminal domains (Nt) configuration of capsid subunits may play in icosahedral nuclear viruses assembly. In synchronous MVM infection, capsid subunits newly assembled as two types of cytoplasmic trimeric intermediates (3VP2, and 1VP1:2VP2) harbored a VP1 phosphorylation level fivefold higher than that of VP2, and hidden Nt. Upon nuclear translocation at S phase, VP1-Nt became exposed in the heterotrimer and subsequent subviral assembly intermediates. Empty capsid subunits showed a phosphorylation level restored to VP1:VP2 stoichiometry, and the Nt concealed in their interior. However ssDNA-filled virus maturing at S/G2 lacked VP1 phosphorylation and one major VP2 phosphopeptide, and exposed VP2-Nt. Endosomal VP2-Nt cleavage resulted in VP3 subunits devoid of any phospholabel, implying that incoming viral particles specifically harbor a low phosphorylation status. Phosphorylation provides a mechanistic coupling of parvovirus nuclear assembly to the cell cycle.
Characterization of H9N2 avian influenza viruses from the Middle East demonstrates heterogeneity at amino acid position 226 in the hemagglutinin and potential for transmission to mammals Virology (IF 3.353) Pub Date : 2018-03-15 Klaudia Chrzastek, Dong-hun Lee, Saad Gharaibeh, Aniko Zsak, Darrell R. Kapczynski
Next-generation sequencing (NGS) technologies are a valuable tool to monitor changes in viral genomes and determine the genetic heterogeneity of viruses. In this study, NGS was applied to clinical poultry samples from Jordan to detect eleven H9N2 low pathogenic avian influenza viruses (LPAIV). All of the viruses tested belonged to Middle East A genetic group of G1 lineage. Deep sequencing demonstrated a high degree of heterogeneity of glutamine and leucine residues at position 226 in the hemagglutinin (HA) gene, which increases specificity to either avian or mammalian-type receptors. Moreover, additional amino acid changes in PB1, PA, M1, M2, and NS1 were identified among the viruses tested. Compared to single gene amplification, application of NGS for surveillance and characterization of H9N2 LPAIV provides a complete genetic profile of emerging isolates and better understanding of the potential of zoonotic transmissions to mammals.
Cellular Hsp27 interacts with classical swine fever virus NS5A protein and negatively regulates viral replication by the NF-κB signaling pathway Virology (IF 3.353) Pub Date : 2018-03-15 Shifeng Ling, Mingyang Luo, Shengnan Jiang, Jiayu Liu, Chunying Ding, Qinghuan Zhang, Huancheng Guo, Wenjie Gong, Changchun Tu, Jinfu Sun
Classical swine fever virus (CSFV) nonstructural protein NS5A is a multifunctional protein functioning in regulation of viral genome replication, protein translation and assembly by interaction with viral or host proteins. Here, heat shock protein 27 (Hsp27) has been identified as a novel binding partner of NS5A by using His tag “pull down” coupled with shotgun LC-MS/MS, with interaction of both proteins further confirmed by co-immunoprecipitation and laser confocal assays. In PK-15 cells, silencing of Hsp27 expression by siRNA enhanced CSFV replication, and upregulation of Hsp27 inhibited viral proliferation. Additionally, we have shown that overexpression of Hsp27 increased NF-κB signaling induced by TNFα. Blocking NF-κB signaling in PK-15 cells overexpressing Hsp27 by ammonium pyrrolidinedithiocarbamate (PDTC) eliminated the inhibition of CSFV replication by Hsp27. These findings clearly demonstrate that the inhibition of CSFV replication by Hsp27 is mediated via the NF-κB signaling pathway.
Enhancement of safety and immunogenicity of the Chinese Hu191 measles virus vaccine by alteration of the S-adenosylmethionine (SAM) binding site in the large polymerase protein Virology (IF 3.353) Pub Date : 2018-03-15 Yilong Wang, Rongxian Liu, Mijia Lu, Yingzhi Yang, Duo Zhou, Xiaoqiang Hao, Dongming Zhou, Bin Wang, Jianrong Li, Yao-Wei Huang, Zhengyan Zhao
The live-attenuated measles virus (MV) vaccine based on the Hu191 strain has played a significant role in controlling measles in China. However, it has considerable adverse effects that may cause public health burden. We hypothesize that the safety and efficacy of MV vaccine can be improved by altering the S-adenosylmethionine (SAM) binding site in the conserved region VI of the large polymerase protein. To test this hypothesis, we established an efficient reverse genetics system for the rMV-Hu191 strain and generated two recombinant MV-Hu191 carrying mutations in the SAM binding site. These two mutants grew to high titer in Vero cells, were genetically stable, and were significantly more attenuated in vitro and in vivo compared to the parental rMV-Hu191 vaccine strain. Importantly, both MV-Hu191 mutants triggered a higher neutralizing antibody than rMV-Hu191 vaccine and provided complete protection against MV challenge. These results demonstrate its potential for an improved MV vaccine candidate.
Serotype-specific restriction of wild-type adenoviruses by the cellular Mre11-Rad50-Nbs1 complex Virology (IF 3.353) Pub Date : 2018-03-15 Neha J. Pancholi, Matthew D. Weitzman
During viral replication in the nucleus, the DNA genomes of adenoviruses are accessible to cellular DNA-binding proteins. Human adenovirus type 5 (Ad5) targets the cellular Mre11-Rad50-Nbs1 complex (MRN) to evade detection by the DNA damage response (DDR). Ad5 mutants that cannot target MRN have reduced viral propagation. Previous studies showed that diverse adenovirus serotypes interact differently with MRN. While these studies revealed diverse MRN interactions among serotypes, it remains unclear how these differences influence viral replication. Here, we examined effects of the DDR on several adenovirus serotypes. We demonstrate that wild-type Ad9 and Ad12 do not overcome MRN impairment. We also examined viral proteins involved in targeting MRN and found that unlike Ad5-E4orf3, expression of Ad9-E4orf3 is not sufficient for MRN mislocalization observed during infection. We conclude that adenovirus serotypes target MRN in distinct ways, and the MRN complex can impair DNA replication of wild-type viruses across the adenovirus family.
Evidence for a novel negative-stranded RNA mycovirus isolated from the plant pathogenic fungus Fusarium graminearum Virology (IF 3.353) Pub Date : 2018-03-15 Luan Wang, Hao He, Shuangchao Wang, Xiaoguang Chen, Dewen Qiu, Hideki Kondo, Lihua Guo
Here we describe a novel (−)ssRNA mycovirus, Fusarium graminearum negative-stranded RNA virus 1 (FgNSRV-1), isolated from Fusarium graminearum strain HN1. The genome of FgNSRV-1 is 9072 nucleotides in length, with five discontinuous but linear ORFs (ORF I-V). Phylogenetic analysis based on entire L polymerase sequences indicated that FgNSRV-1 is related to the (−)ssRNA mycovirus Sclerotinia sclerotiorum negative-stranded RNA virus 1 (SsNSRV-1), and other mycoviruses. Our data suggest that FgNSRV-1 can be classified into the family Mymonaviridae, order Mononegavirales. Putative enveloped virion-like structures with filamentous morphology similar to SsNSRV-1 were observed in virion preparation samples. The L proteins of FgNSRV-1, and other fungal mononegaviruses, were found to be related to L protein-like sequences in some fungal genome, supporting the hypothesis that there is coevolution occurring between mycoviruses and fungi. Besides, clearing the virus from the infected host fungus resulted in no discernable phenotypic change.
Tat controls transcriptional persistence of unintegrated HIV genome in primary human macrophages Virology (IF 3.353) Pub Date : 2018-03-15 Beatrix Meltzer, Deemah Dabbagh, Jia Guo, Fatah Kashanchi, Mudit Tyagi, Yuntao Wu
Identification of nucleotides in the 5’UTR and amino acids substitutions that are essential for the infectivity of 5’UTR-NS5A recombinant of hepatitis C virus genotype 1b (strain Con1) Virology (IF 3.353) Pub Date : 2018-03-15 Jinqian Li, Shengjun Feng, Xi Liu, Mingzhe Guo, Mingxiao Chen, Yiyi Chen, Liang Rong, Jinyu Xia, Yuanping Zhou, Jin Zhong, Yi-Ping Li
Genotype 1b strain Con1 represents an important reference in the study of hepatitis C virus (HCV). Here, we aimed to develop an advanced infectious Con1 recombinant. We found that previously identified mutations A1226G/F1464L/A1672S/Q1773H permitted culture adaption of Con1 Core-NS5A (C-5A) recombinant containing 5’UTR and NS5B-3’UTR from JFH1 (genotype 2a), thus acquired additional mutations L725H/F886L/D2415G. C-5A containing all seven mutations (C-5A_7m) replicated efficiently in Huh7.5 and Huh7.5.1 cells and had an increased infectivity in SEC14L2-expressing Huh7.5.1 cells. Incorporation of Con1 NS5B was deleterious to C-5A_7m, however Con1 5’UTR was permissive but attenuated the virus. Nucleotides G1, A4, and G35 primarily accounted for the viral attenuation without affecting RNA translation. C-5A_7m was inhibited dose-dependently by simeprevir and daclatasvir, and substitutions at A4, A29, A34, and G35 conferred resistance to miR-122 antagonism. The novel Con1 5’UTR-NS5A recombinant, adaptive mutations, and critical nucleotides described here will facilitate future studies of HCV culture systems and virus-host interaction.
Lipid biosensor interactions with wild type and matrix deletion HIV-1 Gag proteins Virology (IF 3.353) Pub Date : 2018-03-15 Eric Barklis, August O. Staubus, Andrew Mack, Logan Harper, Robin Lid Barklis, Ayna Alfadhli
The matrix (MA) domain of the HIV-1 precursor Gag protein (PrGag) has been shown interact with the HIV-1 envelope (Env) protein, and to direct PrGag proteins to plasma membrane (PM) assembly sites by virtue of its affinity to phosphatidylinositol-4,5-bisphosphate (PI[4,5]P2). Unexpectedly, HIV-1 viruses with large MA deletions (ΔMA) have been shown to be conditionally infectious as long as they are matched with Env truncation mutant proteins or alternative viral glycoproteins. To characterize the interactions of wild type (WT) and ΔMA Gag proteins with PI(4,5)P2 and other acidic phospholipids, we have employed a set of lipid biosensors as probes. Our investigations showed marked differences in WT and ΔMA Gag colocalization with biosensors, effects on biosensor release, and association of biosensors with virus-like particles. These results demonstrate an alternative approach to the analysis of viral protein-lipid associations, and provide new data as to the lipid compositions of HIV-1 assembly sites.
Hexon and fiber of adenovirus type 14 and 55 are major targets of neutralizing antibody but only fiber-specific antibody contributes to cross-neutralizing activity Virology (IF 3.353) Pub Date : 2018-03-15 Ying Feng, Xikui Sun, Xianmiao Ye, Yupeng Feng, Jinlin Wang, Xuehua Zheng, Xinglong Liu, Changhua Yi, Mingli Hao, Qian Wang, Feng Li, Wei Xu, Liang Li, Chufang Li, Rong Zhou, Ling Chen, Liqiang Feng
Re-emerging human adenoviruses type 14 (HAdV14) and 55 (HAdV55) represent two highly virulent adenoviruses. The neutralizing antibody (nAb) responses elicited by infection or immunization remain largely unknown. Herein, we generated hexon-chimeric HAdV14 viruses harboring each single or entire hexon hyper-variable-regions (HVR) from HAdV55, and determined the neutralizing epitopes of human and mouse nAbs. In human sera, hexon-targeting nAbs are type-specific and mainly recognize HVR2, 5, and 7. Fiber-targeting nAbs are only detectable in sera cross-neutralizing HAdV14 and HAdV55 and contribute substantially to cross-neutralization. Penton-binding antibodies, however, show no significant neutralizing activities. In mice immunized with HAdV14 or HAdV55, a single immunization mainly elicited hexon-specific nAbs, which recognized HAdV14 HVR1, 2, and 7 and HAdV55 HVR1 and 2, respectively. After a booster immunization, cross-neutralizing fiber-specific nAbs became detectable. These results indicated that hexon elicits type-specific nAbs whereas fiber induces cross-neutralizing nAbs to HAdV14 and HAdV55, which are of significance in vaccine development.
Extending the hosts of Tectiviridae into four additional genera of Gram-positive bacteria and more diverse Bacillus species Virology (IF 3.353) Pub Date : 2018-03-15 Matti Jalasvuori, Katariina Koskinen
Tectiviridae are composed of tailless bacteriophages with an icosahedral capsid and an inner membrane enclosing a double-stranded 15 kb linear DNA genome. Five of the seven previously studied Tectivirus isolates infect bacteria from Bacillus cereus sensu lato group (Betatectivirus), one distantly related member (PRD1) infect Enterobactericeae (Alpatectivirus) and one recently discovered virus infect Gluconobacter cerinus (Gammatectivirus). Here we expand the host spectrum of Betatectivirus elements to four additional genera (Streptococcus, Exiguobacterium, Clostridium and Brevibacillus) and to more distantly related Bacillus species (B. pumilus and B. flexus) by studying the genomes of fourteen novel tectiviral elements. Overall, the genomes show significant conservation in gene synteny and in modules responsible for genome replication and formation of the virion core (including DNA packaging). Notable variation exists in regions encoding host attachment and lysis along with the surrounding area of a site in which mutations are known to alter phage life cycle.
Infection of monocytes with European porcine reproductive and respiratory syndrome virus (PRRSV-1) strain Lena is significantly enhanced by dexamethasone and IL-10 Virology (IF 3.353) Pub Date : 2018-03-02 Helen Singleton, Simon P. Graham, Jean-Pierre Frossard, Katherine B. Bodman-Smith, Falko Steinbach
Monocytes are considered refractory to porcine reproductive and respiratory syndrome virus type 1 (PRRSV-1) infection. However, monocytes are only short-lived in blood, being able to differentiate into macrophages and dendritic cells (DC). It was therefore merited to revisit PRRSV-1 interaction with monocytes, particularly those treated with cytokines influencing monocyte biology. Thus, several factors were screened, particularly those modulating monocyte differentiation and expression of putative PRRSV-1 receptors (CD169 and CD163). M-CSF, known to stimulate macrophage differentiation, did not increase their susceptibility to PRRSV-1. Nor did GM-CSF or IL-4, known drivers for monocyte-derived DC (MoDC) differentiation. In contrast, monocyte treatment with IL-10 or the corticosteroid, dexamethasone, known to be potent suppressors of monocyte differentiation, was correlated with increased susceptibility to PRRSV-1 infection. While this effect was strongly correlated to CD163 and CD169 expression, our data suggest that receptor expression is not the only factor driving successful infection of PPRSV-1 in monocytes.
Aminopeptidase-N-independent entry of porcine epidemic diarrhea virus into Vero or porcine small intestine epithelial cells Virology (IF 3.353) Pub Date : 2018-03-02 Chun-Miao Ji, Bin Wang, Jiyong Zhou, Yao-Wei Huang
A monkey cell line Vero (ATCC CCL-81) is commonly used for porcine epidemic diarrhea virus (PEDV) propagation in vitro. However, it is still controversial whether the porcine aminopeptidase N (pAPN) counterpart on Vero cells (Vero-APN) confers PEDV entry. We found that endogenous expression of Vero-APN was undetectable in the mRNA and the protein levels in Vero cells. We cloned the partial Vero-APN gene (3340-bp) containing exons 1 to 9 from cellular DNA and subsequently generated two APN-knockout Vero cell lines by CRISPR/Cas9 approach. PEDV infection of two APN-knockout Vero cells had the same efficiency as the Vero cells with or without neuraminidase treatment. A Vero cells stably expressing pAPN did not increase PEDV production. SiRNA-knockdown of pAPN in porcine jejunum epithelial cells had no effects on PEDV infection. The results suggest that there exists an additional cellular receptor on Vero or porcine jejunal cells independent of APN for PEDV entry.
Cryo-EM structure of a Marseilleviridae virus particle reveals a large internal microassembly Virology (IF 3.353) Pub Date : 2018-02-23 Kenta Okamoto, Naoyuki Miyazaki, Hemanth K.N. Reddy, Max F. Hantke, Filipe R.N.C. Maia, Daniel S.D. Larsson, Chantal Abergel, Jean-Michel Claverie, Janos Hajdu, Kazuyoshi Murata, Martin Svenda
Spumaretroviruses: Updated taxonomy and nomenclature Virology (IF 3.353) Pub Date : 2018-02-23 Arifa S. Khan, Jochen Bodem, Florence Buseyne, Antoine Gessain, Welkin Johnson, Jens H. Kuhn, Jacek Kuzmak, Dirk Lindemann, Maxine L. Linial, Martin Löchelt, Magdalena Materniak-Kornas, Marcelo A. Soares, William M. Switzer
Spumaretroviruses, commonly referred to as foamy viruses, are complex retroviruses belonging to the subfamily Spumaretrovirinae, family Retroviridae, which naturally infect a variety of animals including nonhuman primates (NHPs). Additionally, cross-species transmissions of simian foamy viruses (SFVs) to humans have occurred following exposure to tissues of infected NHPs. Recent research has led to the identification of previously unknown exogenous foamy viruses, and to the discovery of endogenous spumaretrovirus sequences in a variety of host genomes. Here, we describe an updated spumaretrovirus taxonomy that has been recently accepted by the International Committee on Taxonomy of Viruses (ICTV) Executive Committee, and describe a virus nomenclature that is generally consistent with that used for other retroviruses, such as lentiviruses and deltaretroviruses. This taxonomy can be applied to distinguish different, but closely related, primate (e.g., human, ape, simian) foamy viruses as well as those from other hosts. This proposal accounts for host-virus co-speciation and cross-species transmission.
Behind the scenes of HIV-1 replication: Alternative splicing as the dependency factor on the quiet Virology (IF 3.353) Pub Date : 2018-02-23 Helene Sertznig, Frank Hillebrand, Steffen Erkelenz, Heiner Schaal, Marek Widera
Alternative splicing plays a key role in the HIV-1 life cycle and is essential to maintain an equilibrium of mRNAs that encode viral proteins and polyprotein-isoforms. In particular, since all early HIV-1 proteins are expressed from spliced intronless and late enzymatic and structural proteins from intron containing, i.e. splicing repressed viral mRNAs, cellular splicing factors and splicing regulatory proteins are crucial for the replication capacity. In this review, we will describe the complex network of cis-acting splicing regulatory elements (SREs), which are mainly localized in the neighbourhoods of all HIV‐1 splice sites and warrant the proper ratio of individual transcript isoforms. Since SREs represent binding sites for trans-acting cellular splicing factors interacting with the cellular spliceosomal apparatus we will review the current knowledge of interactions between viral RNA and cellular proteins as well as their impact on viral replication. Finally, we will discuss potential therapeutic approaches targeting HIV-1 alternative splicing.
Characterization of interaction between Trim28 and YY1 in silencing proviral DNA of Moloney murine leukemia virus Virology (IF 3.353) Pub Date : 2018-02-23 Andreia Lee, Oya CingÖz, Yosef Sabo, Stephen P. Goff
Moloney Murine Leukemia Virus (M-MLV) proviral DNA is transcriptionally silenced in embryonic cells by a large repressor complex tethered to the provirus by two sequence-specific DNA binding proteins, ZFP809 and YY1. A central component of the complex is Trim28, a scaffold protein that regulates many target genes involved in cell cycle progression, DNA damage responses, and viral gene expression. The silencing activity of Trim28, and its interactions with corepressors are often regulated by post-translational modifications such as sumoylation and phosphorylation. We defined the interaction domains of Trim28 and YY1, and investigated the role of sumoylation and phosphorylation of Trim28 in mediating M-MLV silencing. The RBCC domain of Trim28 was sufficient for interaction with YY1, and acidic region 1 and zinc fingers of YY1 were necessary and sufficient for its interaction with Trim28. Additionally, we found that residue K779 was critical for Trim28-mediated silencing of M-MLV in embryonic cells.
Detection and phylogenetic analysis of torque teno virus (TTV) carried by murine rodents and house shrews in China Virology (IF 3.353) Pub Date : 2018-02-23 Yi-Quan Xiong, Yun Mo, Ming-Ji Chen, Wei Cai, Wen-Qiao He, Qing Chen
Between May 2015 and May 2017, 496 animals (473 murine rodents and 23 house shrews) were captured in six regions of China. A total of 22.8% (113/496) of throat swabs, 29.1% (142/488) of fecal samples and 23.8% (54/227) of serum samples tested positive for rodent torque teno virus 3 (RoTTV3). The positive rate in Rattus norvegicus was higher than the rate in Rattus tanezumi and Rattus losea. Of 23 house shrews, one throat swab and one serum sample were positive for RoTTV3. Ten murine rodents were simultaneously positive for RoTTV3 in throat swab, fecal and serum samples. Phylogenetic analysis showed that the 12 near-full length genomes of RoTTVs sequences obtained in this study represented a novel RoTTV genotype (RoTTV3). In conclusion, high prevalence rates of RoTTV3 were found in three common murine rodents in China, and the RoTTV3 obtained in this study were classified as a novel genotype of RoTTV.
Phylogenetic and molecular epidemiological studies reveal evidence of recombination among Marek's disease viruses Virology (IF 3.353) Pub Date : 2018-02-23 Liangliang He, Jie Li, Yun Zhang, Jun Luo, Yongchang Cao, Chunyi Xue
Marek's disease has brought enormous loss in chicken production worldwide and the increasing virulence of Marek's disease virus (MDV) became a severe problem. To better understand the genetic basis underlying, a Chinese MDV strain HNGS101 isolated from immunized chickens was sequenced. Phylogenetic analysis implied that HNGS101 showed more relatedness to Eurasian strains than GaHV-2 circulating in North America. Recombination networks analysis showed the evidence of recombination among MDV strains, and several recombination events in the UL and US region were found. Further analysis indicated that the HNGS101 strain seemed to be generated by the recombination of the earliest Eurasian strains and North American strains in the US region, which may be responsible for the MD outbreaks in China. In summary,this is the first report to demonstrate recombination events among MDV strains, which may shed light on the mechanism of virulence enhancement.
Molecular evolution of hepatitis C virus in China: A nationwide study Virology (IF 3.353) Pub Date : 2018-02-23 K. Huang, J. Chen, R. Xu, X. Jiang, X. Ma, M. Jia, M. Wang, J. Huang, Q. Liao, Z. Shan, C. Dailey, X. Song, L. Lu, C. Li, X. Rong, M. Zhang, Y. Fu
The evolutionary and epidemic history and the regional differences of hepatitis C virus (HCV) are complex and remain unclear in the vast territory China. Here we recruited 1540 HCV-RNA positive patients sampled in 29 provinces across whole China, which is the largest sample capacity and the most comprehensive geographic coverage of China to our knowledge. 1b, 2a, 3b, 6a and 3a were the major subtypes in China. 1b was the most predominant subtype which presented in every province. The second most predominant subtype, 2a, appeared to concentrate in the north of China. Subtypes 3a and 3b were mainly found in the Southwest region, while 6a was restricted in the South region. We further estimated the origins of the dominating subtypes and discovered for the first time that a Chinese-specific transmission pattern for some strains of subtype 2a which was restricted in north China, and Chinese subtype 3b originated from Thailand.
Attenuation of Marek's disease virus by codon pair deoptimization of a core gene Virology (IF 3.353) Pub Date : 2018-02-23 Steven J. Conrad, Robert F. Silva, Cari J. Hearn, Megan Climans, John R. Dunn
Marek's disease virus (MDV) is an oncogenic alphaherpesvirus of Gallus gallus, the domesticated chicken. Control strategies rely upon vaccination with live attenuated viruses of antigenically similar avian herpesviruses or attenuated strains of MDV. Recent studies in other viruses have shown that recoding certain viral genes to employ synonymous but rarely-used codon pairs resulted in viral attenuation. We deoptimized two MDV proteins, UL54/ICP27 and UL49/VP22, and demonstrate that the more severely deoptimized variant of UL54 accumulates significantly less gene product in vitro. Using these UL54 deoptimized mutants, we further demonstrate that animals infected with the UL54-recoded recombinant virus exhibited decreased viral genome copy number in lymphocytes, reduced lymphoid atrophy and reduced tumor incidence. This study demonstrates that codon pair deoptimization of a single viral gene can produce attenuated strains of MDV. This approach may be useful as a rational way of making novel live attenuated virus vaccines for MDV.
Isolation, characterization and prevalence of a novel Gammaherpesvirus in Eptesicus fuscus, the North American big brown bat Virology (IF 3.353) Pub Date : 2018-02-23 Sonu Subudhi, Noreen Rapin, Nicole Dorville, Janet E. Hill, Jennifer Town, Craig K.R. Willis, Trent K. Bollinger, Vikram Misra
Little is known about the relationship of Gammaherpesviruses with their bat hosts. Gammaherpesviruses are of interest because of their long–term infection of lymphoid cells and their potential to cause cancer. Here, we report the characterization of a novel bat herpesvirus isolated from a big brown bat (Eptesicus fuscus) in Canada. The genome of the virus, tentatively named Eptesicus fuscus herpesvirus (EfHV), is 166,748 base pairs. Phylogenetically EfHV is a member of Gammaherpesvirinae, in which it belongs to the Genus Rhadinovirus and is closely related to other bat Gammaherpesviruses. In contrast to other known Gammaherpesviruses, the EfHV genome contains coding sequences similar to those of class I and II host major histocompatibility antigens. The virus is capable of infecting and replicating in human, monkey, cat and pig cell lines. Although we detected EfHV in 20 of 28 big brown bats tested, these bats lacked neutralizing antibodies against the virus.
Proteomic profiling of HIV-infected T-cells by SWATH mass spectrometry Virology (IF 3.353) Pub Date : 2018-02-23 Jason DeBoer, Melinda S. Wojtkiewicz, Nicole Haverland, Yan Li, Emma Harwood, Emily Leshen, Joseph W. George, Pawel Ciborowski, Michael Belshan
Viral pathogenesis results from changes in host cells due to virus usurpation of the host cell and the innate cellular responses to thwart infection. We measured global changes in protein expression and localization in HIV-1 infected T-cells using subcellular fractionation and the Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS) proteomic platform. Eight biological replicates were performed in two independent experimental series. In silico merging of both experiments identified 287 proteins with altered expression (p < .05) between control and infected cells- 172 in the cytoplasm, 84 in the membrane, and 31 in nuclei. 170 of the proteins are components of the NIH HIV interaction database. Multiple Reaction Monitoring and traditional immunoblotting validated the altered expression of several factors during infection. Numerous factors were found to affect HIV infection in gain- and loss-of-expression infection assays, including the intermediate filament vimentin which was found to be required for efficient infection.
Differences in dynamics of horizontal transmission of Tomato planta macho viroid and Potato spindle tuber viroid after pollination with viroid-infected pollen Virology (IF 3.353) Pub Date : 2018-02-23 Hironobu Yanagisawa, Yosuke Matsushita
For viroids, pollen transmission is an important transmission pathway to progeny seeds and new hosts. In the current study, we found that Tomato planta macho viroid (TPMVd)—but not Potato spindle tuber viroid (PSTVd)—was horizontally transmitted by pollen from petunia plants. Using tissue-printing hybridization to track the changes in viroid distribution after pollination, we noted that TPMVd was present in petunia stigma, styles, and eventually ovaries, whereas PSTVd was detected in the stigma and upper style but not the ovary. These findings suggest that horizontal transmission of viroids depends on the infection of the lower style and ovary during the elongation of pollen tubes after pollination. Additionally, TPMVd was transmitted horizontally, leading to systematic infection, when we used TPMVd-infected petunia pollen to pollinate the flowers of healthy tomato plants. Fertilization typically does not occur after heterologous pollination and thus likely is not required to accomplish horizontal transmission of viroids.
Analysis of enterovirus types in patients with symptoms of aseptic meningitis in 2014 in Shandong, China Virology (IF 3.353) Pub Date : 2018-02-23 Peng Chen, Xiaojuan Lin, Guifang Liu, Suting Wang, Lizhi Song, Zexin Tao, Aiqiang Xu
We reviewed the epidemiological and clinical characteristics of 927 aseptic meningitis patients in Shandong in 2014, and the phylogeny of predominant enterovirus (EV) types causing this disease was analyzed. A total of 209 patients that were positive for EV were identified by both cell culture and a reverse transcription-seminested PCR in cerebrospinal fluid samples. The positive patients were most likely to be children within 15 years of age, had symptoms such as fever, vomiting and nausea (P＜ .05). The 209 EV sequences belonged to 11 types, and coxsackievirus B5, echovirus types 6 and 30 were predominant types. VP1 analysis exhibited multiple lineages were co-circulating. The significance of the study could come from the fact that surveillance is important to monitor the prevalence of EV types in population, which shows enterovirus meningitis maintains an important public health problem in China.
Comprehensive virome analysis reveals the complexity and diversity of the viral spectrum in pediatric patients diagnosed with severe and mild hand-foot-and-mouth disease Virology (IF 3.353) Pub Date : 2018-02-19 Chunhua Wang, Shuaifeng Zhou, Wanhua Xue, Liang Shen, Wei Huang, Yi Zhang, Xuguang Li, Junzhi Wang, Hong Zhang, Xuejun Ma
The management of hand-foot-and-mouth disease(HFMD) epidemic is difficult due to the frequent emergence of non-EV71 and non-CVA16 enteroviruses and some cases testing negative for HFMD-associated causative agents. To clarify the virus spectrum of mild and severe HFMD, a comprehensive virome analysis of 238 samples was performed using next-generation sequencing (NGS). The data revealed total thirteen mammalian- and plant- virus families and diverse viral populations including enteroviruses, common respiratory viruses, diarrhea-related viruses, plant viruses and anelloviruses. A total of 18 viruses from 7 virus families were identified in severe cases, versus 37 viruses from 12 virus families in mild cases. Moreover, complicated mixed-infections of enteroviruses with common respiratory viruses were mainly found in severe cases(P = 0.013), while diarrhea-related viruses were mainly found in mild cases(P < 0.001). This study provides the preliminary understanding of viromes both in mild and severe cases, which may benefit the detection of etiologic agents and prevention of HFMD.
The structural proteins of epidemic and historical strains of Zika virus differ in their ability to initiate viral infection in human host cells Virology (IF 3.353) Pub Date : 2018-02-01 Sandra Bos, Wildriss Viranaicken, Jonathan Turpin, Chaker El-Kalamouni, Marjolaine Roche, Pascale Krejbich-Trotot, Philippe Desprès, Gilles Gadea
Mosquito-borne Zika virus (ZIKV) recently emerged in South Pacific islands and Americas where large epidemics were documented. In the present study, we investigated the contribution of the structural proteins C, prM and E in the permissiveness of human host cells to epidemic strains of ZIKV. To this end, we evaluated the capacity of the epidemic strain BeH819015 to infect epithelial A549 and neuronal SH-SY5Y cells in comparison to the African historical MR766 strain. For that purpose, we generated a molecular clone of BeH819015 and a chimeric clone of MR766 which contains the BeH819015 structural protein region. We showed that ZIKV containing BeH819015 structural proteins was much less efficient in cell-attachment leading to a reduced susceptibility of A549 and SH-SY5Y cells to viral infection. Our data illustrate a previously underrated role for C, prM, and E in ZIKV epidemic strain ability to initiate viral infection in human host cells.
The roles of five conserved lentiviral RNA structures in HIV-1 replication Virology (IF 3.353) Pub Date : 2017-11-09 Yang Liu, Jianbo Chen, Olga A. Nikolaitchik, Belete A. Desimmie, Steven Busan, Vinay K. Pathak, Kevin M. Weeks, Wei-Shau Hu
The HIV-1 RNA genome contains complex structures with many structural elements playing regulatory roles during viral replication. A recent study has identified multiple RNA structures with unknown functions that are conserved among HIV-1 and two simian immunodeficiency viruses. To explore the roles of these conserved RNA structures, we introduced synonymous mutations into the HIV-1 genome to disrupt each structure. These mutants exhibited similar particle production, viral infectivity, and replication kinetics relative to the parent NL4-3 virus. However, when replicating in direct competition with the wild-type NL4-3 virus, mutations of RNA structures at inter-protein domain junctions can cause fitness defects. These findings reveal the ability of HIV-1 to tolerate changes in its sequences, even in apparently highly conserved structures, which permits high genetic diversity in HIV-1 population. Our results also suggest that some conserved RNA structures may function to fine-tune viral replication.
Retargeted and detargeted adenovirus for gene delivery to the muscle Virology (IF 3.353) Pub Date : 2017-11-22 Tien V. Nguyen, Stephanie S. Anguiano-Zarate, William E. Matchett, Mary E. Barry, Michael A. Barry
We previously selected muscle binding peptides 12.51 and 12.52 from "context-specific" phage display libraries for introduction into adenovirus (Ad) vectors. In this work, these peptides were inserted into the hypervariable region (HVR) 5 loop of the Ad5 hexon protein to display 720 peptides per virions. HVR-12.51 and 12.52 increased transduction of C2C12 cells up to 20-fold when compared to unmodified Ad5. 12.51 increased in vivo muscle transduction 2 to 7-fold over unmodified Ad after intramuscular injection in mice and hamsters. 12.52 did not increase muscle transduction. Notably, insertion of 12.51 into the hexon reduced liver transduction 80-fold when compared to unmodified Ad5 after intravenous injection. Increased muscle transduction in mice translated into increased immune responses after gene-based vaccination. These data suggest there are merits to retargeting and detargeting benefits to modifying the hexons of Ads with peptide ligands.
Increases in the competitive fitness of West Nile virus isolates after introduction into California Virology (IF 3.353) Pub Date : 2017-11-28 Gabriella Worwa, Andra A. Hutton, Michèle Frey, Nisha K. Duggal, Aaron C. Brault, William K. Reisen
Discovery of novel anelloviruses in small mammals expands the host range and diversity of the Anelloviridae Virology (IF 3.353) Pub Date : 2017-11-10 William Marciel de Souza, Marcílio Jorge Fumagalli, Jansen de Araujo, Gilberto Sabino-Santos, Felipe Gonçalves Motta Maia, Marilia Farignoli Romeiro, Sejal Modha, Marcello Schiavo Nardi, Luzia Helena Queiroz, Edison Luiz Durigon, Márcio Roberto Teixeira Nunes, Pablo Ramiro Murcia, Luiz Tadeu Moraes Figueiredo
The Anelloviridae comprises single-stranded DNA viruses currently grouped in sixty-eight species classified in twelve genera. They have been found in many vertebrate hosts including primates. In this study, we describe the application of the high-throughput sequencing to examine the frequency and diversity of anelloviruses in rodents, bats and opossums captured in São Paulo State, Brazil. We report a total of twenty-six anelloviruses with sixteen nearly complete genomes and ten partial genomes, which include eleven potential novel species identified in rodents (Cricetidae), bats (Molossidae and Phyllostomidae), and opossums (Didelphidae). We also propose the inclusion of two potential new genera within the Anelloviridae family, provisionally named Omegatorquevirus and Sigmatorquevirus, including six and three novel species of anelloviruses, respectively. In summary, this study expands the diversity and the host range of the known anelloviruses.
Rab1A is required for assembly of classical swine fever virus particle Virology (IF 3.353) Pub Date : 2017-11-10 Jihui Lin, Chengbao Wang, Wulong Liang, Jing Zhang, Longxiang Zhang, Huifang Lv, Wang Dong, Yanming Zhang
Rab1A belongs to the small Rab GTPase family and is involved in the lifecycle of numerous viruses. Here, knockdown of Rab1A inhibited CSFV growth. Further study revealed that Rab1A depletion decreased intracellular and extracellular CSFV titers, but did not affect intracellular virus genome copies and E2 protein expression within a virus lifecycle, which suggested that Rab1A is required for CSFV particle assembly rather than for genome replication or virion release. This was proofed by blocking the spread of virus using neutralizing antibodies, through which the negative effects of Rab1A knockdown on multi-cycle replication of CSFV were eliminated. Moreover, co-immunoprecipitation and confocal microscopy assays showed that Rab1A bound to CSFV NS5A protein, indicating that Rab1A and viral NS5A proteins may work cooperatively during CSFV particle assembly. In conclusion, this study demonstrated for the first time that Rab1A is required for CSFV particle assembly and binds to viral particle assembly-related NS5A protein.
Development and characterization of a human monoclonal antibody targeting the N-terminal region of hepatitis C virus envelope glycoprotein E1 Virology (IF 3.353) Pub Date : 2017-11-10 Ahmed Atef Mesalam, Isabelle Desombere, Ali Farhoudi, Freya Van Houtte, Lieven Verhoye, Jonathan Ball, Jean Dubuisson, Steven K.H. Foung, Arvind H. Patel, Mats A.A. Persson, Geert Leroux-Roels, Philip Meuleman
Monoclonal antibodies (mAbs) targeting the hepatitis C virus (HCV) envelope have been raised mainly against envelope protein 2 (E2), while the antigenic epitopes of envelope protein 1 (E1) are not fully identified. Here we describe the detailed characterization of a human mAb, designated A6, generated from an HCV genotype 1b infected patient. ELISA results showed reactivity of mAb A6 to full-length HCV E1E2 of genotypes 1a, 1b and 2a. Epitope mapping identified a region spanning amino acids 230–239 within the N-terminal region of E1 as critical for binding. Antibody binding to this epitope was not conformation dependent. Neutralization assays showed that mAb A6 lacks neutralizing capacity and does not interfere with the activity of known neutralizing antibodies. In summary, mAb A6 is an important tool to study the structure and function of E1 within the viral envelope, a crucial step in the development of an effective prophylactic HCV vaccine.
Wheat streak mosaic virus coat protein is a determinant for vector transmission by the wheat curl mite Virology (IF 3.353) Pub Date : 2017-11-10 Satyanarayana Tatineni, Anthony J. McMechan, Gary L. Hein
Wheat streak mosaic virus (WSMV; genus Tritimovirus; family Potyviridae), is transmitted by the wheat curl mite (Aceria tosichella Keifer). The requirement of coat protein (CP) for WSMV transmission by the wheat curl mite was examined using a series of viable deletion and point mutations. Mite transmission of WSMV was completely abolished with deletions comprising CP amino acids 58–100. In contrast, the amino-proximal (amino acids 6–27 and 36–57) and carboxy-terminal (14 amino acids) regions of CP were expendable for mite transmission. Mutation of aspartic acid residues at amino acid positions 289 or 326 (D289A or D326A) at the carboxy-proximal region of CP significantly reduced mite transmission. Remarkably, every wheat plant infected by mutants D289A or D326A through mite transmission but not with in vitro transcripts contained a second-site mutation of R131C and N275H, respectively. Collectively, these data demonstrate for the first time that CP is a determinant for an eriophyid-transmitted plant virus.
VPg unlinkase/TDP2 in cardiovirus infected cells: Re-localization and proteolytic cleavage Virology (IF 3.353) Pub Date : 2018-01-30 Sonia Maciejewski, Wendy Ullmer, Bert L. Semler
Cardioviruses cause diseases in many animals including, in rare cases, humans. Although they share common features with all picornaviruses, cardioviruses have unique properties that distinguish them from other family members, including enteroviruses. One feature shared by all picornaviruses is the covalent attachment of VPg to the 5′ end of genomic RNA via a phosphotyrosyl linkage. For enteroviruses, this linkage is cleaved by a host cell protein, TDP2. Since TDP2 is divergently required during enterovirus infections, we determined if TDP2 is necessary during infection by the prototype cardiovirus, EMCV. We found that EMCV yields are reduced in the absence of TDP2. We observed a decrease in viral protein accumulation and viral RNA replication in the absence of TDP2. In contrast to enterovirus infections, we found that TDP2 is modified at peak times of EMCV infection. This finding suggests a unique mechanism for cardioviruses to regulate TDP2 activity during infection.
Schmallenberg virus non-structural protein NSm: Intracellular distribution and role of non-hydrophobic domains Virology (IF 3.353) Pub Date : 2018-01-09 Franziska Kraatz, Kerstin Wernike, Sven Reiche, Andrea Aebischer, Ilona Reimann, Martin Beer
Schmallenberg virus (SBV) induces fetal malformation, abortions and stillbirth in ruminants. While the non-structural protein NSs is a major virulence factor, the biological function of NSm, the second non-structural protein which consists of three hydrophobic transmembrane (I, III, V) and two non-hydrophobic regions (II, IV), is still unknown. Here, a series of NSm mutants displaying deletions of nearly the entire NSm or of the non-hydrophobic domains was generated and the intracellular distribution of NSm was assessed. SBV-NSm is dispensable for the generation of infectious virus and mutants lacking domains II – V showed growth properties similar to the wild-type virus. In addition, a comparable intracellular distribution of SBV-NSm was observed in mammalian cells infected with domain II mutants or wild-type virus. In both cases, NSm co-localized with the glycoprotein Gc in the Golgi compartment. However, domain IV-deletion mutants showed an altered distribution pattern and no co-localization of NSm and Gc.
The interactome of EBV LMP1 evaluated by proximity-based BioID approach Virology (IF 3.353) Pub Date : 2018-01-09 Mark A. Rider, Mujeeb R. Cheerathodi, Stephanie N. Hurwitz, Dingani Nkosi, Lauren A. Howell, Deanna C. Tremblay, Xia Liu, Fanxiu Zhu, David G. Meckes
Epstein-Barr virus LMP1 is an oncoprotein required for immortalizing B lymphocytes and also plays important roles in transforming non-lymphoid tissue. The discovery of LMP1 protein interactions will likely generate targets to treat EBV-associated cancers. Here, we define the broader LMP1 interactome using the recently developed BioID method. Combined with mass spectrometry, we identified over 1000 proteins across seven independent experiments with direct or indirect relationships to LMP1. Pathway analysis suggests that a significant number of the proteins identified are involved in signal transduction and protein or vesicle trafficking. Interestingly, a large number of proteins thought to be important in the formation of exosomes and protein targeting were recognized as probable LMP1 interacting partners, including CD63, syntenin-1, ALIX, TSG101, HRS, CHMPs, and sorting nexins. Therefore, it is likely that LMP1 modifies protein trafficking and exosome biogenesis pathways. In support of this, knock-down of syntenin-1 and ALIX resulted in reduced exosomal LMP1.
Identification of novel amino acid residues of influenza virus PA-X that are important for PA-X shutoff activity by using yeast Virology (IF 3.353) Pub Date : 2018-01-10 Kohei Oishi, Seiya Yamayoshi, Yoshihiro Kawaoka
The influenza A virus protein PA-X comprises an N-terminal PA region and a C-terminal PA-X-specific region. PA-X suppresses host gene expression, termed shutoff, via mRNA cleavage. Although the endonuclease active site in the N-terminal PA region of PA-X and basic amino acids in the C-terminal PA-X-specific region are known to be important for PA-X shutoff activity, other amino acids may also play a role. Here, we used yeast to identify novel amino acids of PA-X that are important for PA-X shutoff activity. Unlike wild-type PA-X, most PA-X mutants predominantly localized in the cytoplasm, indicating that these mutations decreased the shutoff activity of PA-X by affecting PA-X translocation to the nucleus. Mapping of the identified amino acids onto the N-terminal structure of PA revealed that some of them likely contribute to the formation of the endonuclease active site of PA.
Development of a novel equine influenza virus live-attenuated vaccine Virology (IF 3.353) Pub Date : 2018-01-11 Laura Rodriguez, Stephanie Reedy, Aitor Nogales, Pablo R. Murcia, Thomas M. Chambers, Luis Martinez-Sobrido
H3N8 equine influenza virus (EIV) is an important and significant respiratory pathogen of horses. EIV is enzootic in Europe and North America, mainly due to the suboptimal efficacy of current vaccines. We describe, for the first time, the generation of a temperature sensitive (ts) H3N8 EIV live-attenuated influenza vaccine (LAIV) using reverse-genetics approaches. Our EIV LAIV was attenuated (att) in vivo and able to induce, upon a single intranasal administration, protection against H3N8 EIV wild-type (WT) challenge in both a mouse model and the natural host, the horse. Notably, since our EIV LAIV was generated using reverse genetics, the vaccine can be easily updated against drifting or emerging strains of EIV using the safety backbone of our EIV LAIV as master donor virus (MDV). These results demonstrate the feasibility of implementing a novel EIV LAIV approach for the prevention and control of currently circulating H3N8 EIVs in horse populations.
Classification and evolution of human papillomavirus genome variants: Alpha-5 (HPV26, 51, 69, 82), Alpha-6 (HPV30, 53, 56, 66), Alpha-11 (HPV34, 73), Alpha-13 (HPV54) and Alpha-3 (HPV61) Virology (IF 3.353) Pub Date : 2018-01-11 Zigui Chen, Mark Schiffman, Rolando Herrero, Rob DeSalle, Kathryn Anastos, Michel Segondy, Vikrant V. Sahasrabuddhe, Patti E. Gravitt, Ann W. Hsing, Paul K.S. Chan, Robert D. Burk
HPV variants from the same type can be classified into lineages and sublineages based on the complete genome differences and the phylogenetic topologies. We examined nucleotide variations of twelve HPV types within the species Alpha-5 (HPV26, 51, 69, 82), Alpha-6 (HPV30, 53, 56, 66), Alpha-11 (HPV34, 73), Alpha-13 (HPV54) and Alpha-3 (HPV61) by analyzing 1432 partial sequences and 181 complete genomes from multiple geographic populations. The inter-lineage and inter-sublineage mean differences of HPV variants ranged between 0.9–7.3% and 0.3–0.9%, respectively. The heterogeneity and phylogenies of HPV isolates indicate an independent evolutionary history for each type. The noncoding regions were the most variable regions whereas the capsid proteins were relatively conserved. Certain variant lineages and/or sublineages were geographically-associated. These data provide the basis to further classify HPV variants and should foster future studies on the evolution of HPV genomes and the associations of HPV variants with cancer risk.
Structure-based assessment of protein-protein interactions and accessibility of protein IX in adenoviruses with implications for antigen display Virology (IF 3.353) Pub Date : 2018-01-11 Nathaniel L. Matteson, Michael A. Barry, Vijay S. Reddy
The exterior minor protein IX of adenoviruses (AdVs) is a frequent target of attachment of antigens and the modified AdVs are being used as potent vaccine platforms. The organization of protein IX is disticntly different between human adenoviruses (HAdVs) and non-HAdVs. The analysis of solvent accessibility, based on the near atomic resolution structures, suggests that the C-terminal residues of IX are more accessible in non-HAdVs (e.g., bovine adenovirus) than in HAdVs. Although the C-terminal fusions of IX are displayed on the capsid surface, they could disrupt the formation of tetrameric coiled-coils (4-HLXB) in HAdVs due to steric hinderance, thereby potentially affecting the capsid stability. Importantly, the parallel-antiparallel arrangement of helices seen in the 4-HLXB is not condusive for IX C-terminal fusions in HAdVs. In contrast, the parallel trimeric C-terminal coiled-coils in non-HAdVs are unlikely to be affected by the attachment of antigens and more efficiently displayed on the AdV surface.
A partial deletion within foot-and-mouth disease virus non-structural protein 3A causes clinical attenuation in cattle but does not prevent subclinical infection Virology (IF 3.353) Pub Date : 2018-01-12 Carolina Stenfeldt, Jonathan Arzt, Juan M. Pacheco, Douglas P. Gladue, George R. Smoliga, Ediane B. Silva, Luis L. Rodriguez, Manuel V. Borca
Deletions within the 3A coding region of foot-and-mouth disease virus (FMDV) are associated with decreased virulence in cattle; however, the mechanisms are unknown. We compared experimental infection of cattle with virulent FMDV O1Campos (O1Ca) and a mutant derivative (O1Ca∆3A) lacking residues 87–106 of 3A. Unexpectedly, primary infection of the nasopharyngeal mucosa was similar for both viruses. However, while O1Ca caused viremia and fulminant clinical disease, O1Ca∆3A infection was subclinical and aviremic. There were no differences in expression of anti-viral cytokines in nasopharyngeal tissues between the groups, suggesting attenuation by O1Ca∆3A was a consequence of reduced replication efficiency in bovine cells, rather than a difference in the host response. These results demonstrated that although deletion in 3A of FMDV confers a clinically attenuated phenotype in cattle, the deletion does not prevent subclinical infection. These findings have implications for field scenarios involving outbreaks with apparently host-limited strains of FMDV.
Extensive conservation of prokaryotic ribosomal binding sites in known and novel picobirnaviruses Virology (IF 3.353) Pub Date : 2018-01-12 Siddharth R. Krishnamurthy, David Wang
Currently, the Leviviridae and Cystoviridae are the only two recognized families of prokaryotic RNA viruses. Picobirnaviruses, which are bisegmented double-stranded RNA viruses commonly found in animal stool samples, are currently thought to be animal viruses, but have not been propagated in cell culture or in an animal model. We hypothesize that picobirnaviruses are prokaryotic RNA viruses. We identified and analyzed the genomes of 38 novel picobirnaviruses and determined that a classical bacterial sequence motif, the ribosomal binding site (RBS), is present in the 5′ untranslated regions (5′ UTRs) of all of the novel as well as all previously published picobirnavirus sequences. Among all viruses, enrichment of the RBS motif is only observed in viral families that infect prokaryotes and not in eukaryotic infecting viral families. These results will enable future studies to more accurately understand the biology of picobirnaviruses.
Human Papillomavirus E6 interaction with cellular PDZ domain proteins modulates YAP nuclear localization Virology (IF 3.353) Pub Date : 2018-01-12 Sydney Webb Strickland, Nicole Brimer, Charles Lyons, Scott B. Vande Pol
HPV E6 oncoproteins associate with cellular PDZ proteins. In addition to previously identified cellular PDZ proteins, we found association of the HPV16 E6 PBM with the Dystrophin Glycoprotein Complex, LRCC1, and SLC9A3R2. HPV18 E6 had additional associations when lysates from adenomatous cell lines were used including LRPPRC, RLGAPB, EIF3A, SMC2 and 3, AMOT, AMOTL1, and ARHGEF1; some of these cellular PDZ proteins are implicated in the regulation of the YAP1 transcriptional co-activator. In keratinocytes, nuclear translocation of YAP1 was promoted by the complete HPV-16 genome, or by expression of the individual E6 or E7 oncoproteins; the activity of E6 required an intact PBM at the carboxy-terminus. This work demonstrates that E6 association with cellular PDZ proteins promotes the nuclear localization of YAP1. The ability of E6 to promote the nuclear transport of YAP1 thus identifies an E6 activity that could contribute to the transformation of cells by E6.
Expression of flavivirus capsids enhance the cellular environment for viral replication by activating Akt-signalling pathways Virology (IF 3.353) Pub Date : 2018-01-19 Adriana M. Airo, Matt D. Urbanowski, Joaquin Lopez-Orozco, Jae Hwan You, Tamara D. Skene-Arnold, Charles Holmes, Vladimir Yamshchikov, Natasha Malik-Soni, Lori Frappier, Tom C. Hobman
Flaviviruses depend on multiple host pathways during their life cycles and have evolved strategies to avoid the innate immune response. Previously, we showed that the West Nile virus capsid protein plays a role in this process by blocking apoptosis. In this study, we examined how expression of capsid proteins from several flaviviruses affects apoptosis and other host processes that impact virus replication. All of the tested capsid proteins protected cells from Fas-dependent apoptosis through a mechanism that requires activated Akt. Capsid expression upregulated other Akt-dependent cellular processes including expression of glucose transporter 1 and mitochondrial metabolism. Protein phosphatase 1, which is known to inactivate Akt, was identified as a DENV capsid interacting protein. This suggests that DENV capsid expression activates Akt by sequestering phosphatases that downregulate phospho-Akt. Capsid-dependent upregulation of Akt would enhance downstream signalling pathways that affect cell survival and metabolism, thus providing a favourable environment for virus replication.
Regulatory CD4 T cells inhibit HIV-1 expression of other CD4 T cell subsets via interactions with cell surface regulatory proteins Virology (IF 3.353) Pub Date : 2018-01-08 Mingce Zhang, Tanya O. Robinson, Alexandra Duverger, Olaf Kutsch, Sonya L. Heath, Randy Q. Cron
Progress toward an enhanced vaccine: Eight marked attenuated viruses to porcine reproductive and respiratory disease virus Virology (IF 3.353) Pub Date : 2018-01-08 Allyn Spear, Feng-Xue Wang, Matthew A. Kappes, Phani B. Das, Kay S. Faaberg
Recombinant viruses of strain Ingelvac® PRRS porcine reproductive and respiratory syndrome virus (PRRSV) modified live virus vaccine were produced with two individual small in-frame deletions in nonstructural protein 2 (nsp2; Δ23 and Δ87) and also the same deletions supplanted with foreign tags (Δ23-V5, Δ23-FLAG, Δ23-S, Δ87-V5, Δ87-FLAG, Δ87-S). The viruses, but one (Δ87-FLAG), were stable for 10 passages and showed minimal effects on in vitro growth. Northern hybridization showed that the Δ23–tagged probe detected intracellular viral genome RNA as well as shorter RNAs that may represent heteroclite species, while the Δ87-tagged probe detected predominantly only genome length RNAs. When the tagged viruses were used to probe nsp2 protein in infected cells, perinuclear localization similar to native nsp2 was seen. Dual infection of Δ23-S and Δ87-S viruses allowed some discrimination of individual tagged nsp2 protein, facilitating future research. The mutants could potentially also be used to differentiate infected from vaccinated animals.
Evaluation of the zoonotic potential of multiple subgroups of clade 188.8.131.52 influenza A (H5N8) virus Virology (IF 3.353) Pub Date : 2018-01-08 Yu-Na Lee, Eun-Kyoung Lee, Byung-Min Song, Gyeong-Beom Heo, Sang-Hee Woo, Sun-Ha Cheon, Youn-Jeong Lee
Clade 184.108.40.206 H5N8 highly pathogenic avian influenza viruses (HPAIVs) have spread worldwide. Phylogenetic analysis identified two genetic groups of the H5N8 HPAIVs in South Korea; group A evolved further into four subgroups. Here, we examined the zoonotic potential, both in vivo and in vitro, of genetically distinct subgroups of H5N8 HPAIVs isolated in South Korea. When compared with other subgroups, A/mallard/Korea/H2102/2015 (H2102) virus caused relatively severe disease in mice at high doses. In ferrets, all H5N8 viruses replicated restrictively in the respiratory tract and did not induce significant clinical signs of influenza infection. In vitro studies, all viruses displayed a hemagglutinin phenotype that was poorly adapted for infection of mammals, although the H2102 virus exhibited higher replication kinetics at 33 °C than the others. Although H5N8 HPAIVs have not yet acquired all the characteristics required for adaptation to mammals, their ability to evolve continuously underscores the need for timely risk assessment.
Phylogenetic analysis reveals three distinct epidemiological profiles in Dutch and Flemish blood donors with hepatitis B virus infection Virology (IF 3.353) Pub Date : 2018-01-08 Thijs J. van de Laar, Véronique A. Van Gaever, Peter van Swieten, An Muylaert, Veerle Compernolle, Hans L. Zaaijer
During 2006–2016, hepatitis B virus (HBV) was detected in nearly 400 blood donors in the Netherlands and Flanders. Donor demographics and self-reported risk factors as disclosed during the donor exit interview were compared to HBV phylogenies of donor and reference sequences. First-time donors with chronic HBV-infection were often immigrants (67%) infected with genetically highly diverse strains of genotypes A (32%), B (8%), C (6%), D (53%) and E to H (1%). Each subtype was strongly associated with donor ethnicity. In contrast, 57/62 (93%) of acute/recent HBV infections occurred among indigenous donors, of whom 67% was infected with one specific widely circulating epidemic HBV-A2 lineage. HBV typing identified three distinct epidemiological profiles: the import of chronic HBV infections through migration, longstanding transmission of non-epidemic HBV-A2 strains within western-Europe, and the active transmission of one epidemic HBV-A2 strain most likely fueled by sexual risk behavior.
Ross River virus envelope glycans contribute to disease through activation of the host complement system Virology (IF 3.353) Pub Date : 2018-01-08 Bronwyn M. Gunn, Jennifer E. Jones, Reed S. Shabman, Alan C. Whitmore, Sanjay Sarkar, Lance K. Blevins, Thomas E. Morrison, Mark T. Heise
Mannose binding lectin (MBL) generally plays a protective role during viral infection, yet MBL-mediated complement activation promotes Ross River virus (RRV)-induced inflammatory tissue destruction, contributing to arthritis and myositis. As MBL binds to carbohydrates, we hypothesized that N-linked glycans on the RRV envelope glycoproteins act as ligands for MBL. Using a panel of RRV mutants lacking the envelope N-linked glycans, we found that MBL deposition onto infected cells was dependent on the E2 glycans. Moreover, the glycan-deficient viruses exhibited reduced disease and tissue damage in a mouse model of RRV-induced myositis compared to wild-type RRV, despite similar viral load and inflammatory infiltrates within the skeletal muscle. Instead, the reduced disease induced by glycan-deficient viruses was linked to decreased MBL deposition and complement activation within inflamed tissues. These results demonstrate that the viral N-linked glycans promote MBL deposition and complement activation onto RRV-infected cells, contributing to the development of RRV-induced myositis.
Molecular dissection of distinct symptoms induced by tomato chlorosis virus and tomato yellow leaf curl virus based on comparative transcriptome analysis Virology (IF 3.353) Pub Date : 2018-01-06 Jang-Kyun Seo, Mi-Kyeong Kim, Hae-Ryun Kwak, Hong-Soo Choi, Moon Nam, Junkyoung Choe, Boram Choi, Soo-Jung Han, Jin-Ho Kang, Choonkyun Jung
The viral infection of plants may cause various physiological symptoms associated with the reprogramming of plant gene expression. However, the molecular mechanisms and associated genes underlying disease symptom development in plants infected with viruses are largely unknown. In this study, we employed RNA sequencing for in-depth molecular characterization of the transcriptional changes associated with the development of distinct symptoms induced by tomato chlorosis virus (ToCV) and tomato yellow leaf curl virus (TYLCV) in tomato. Comparative analysis of differentially expressed genes revealed that ToCV and TYLCV induced distinct transcriptional changes in tomato and resulted in the identification of important genes responsible for the development of symptoms of ToCV (i.e., chlorosis and anthocyanin accumulation) and TYLCV (i.e., yellowing, stunted growth, and leaf curl). Our comprehensive transcriptome analysis can provide molecular strategies to reduce the severity of disease symptoms as well as new insights for the development of virus-resistant crops.
Zika viral infection and neutralizing human antibody response in a BLT humanized mouse model Virology (IF 3.353) Pub Date : 2018-01-06 Kimberly Schmitt, Paige Charlins, Milena Veselinovic, Lauren Kinner-Bibeau, Shuang Hu, James Curlin, Leila Remling-Mulder, Ken E. Olson, Tawfik Aboellail, Ramesh Akkina
Many murine and non-human primate animal models have been recently developed to understand Zika viral pathogenesis. However, a major limitation with these models is the inability to directly examine the human-specific immune response. Here, we utilized a BLT humanized mouse model endowed with a transplanted human immune system. Plasma viremia could be detected within 48 h after viral challenge and viremia persisted for as long as 220 days in some mice. Neutralizing human antibody was detected in infected mice and mouse sera showed reactivity with the viral envelope and capsid proteins in a radio-immunoprecipitation assay. Human monocytes/macrophages, B cells and hematopoietic stem cells in the bone marrow were found to be virus infected. These data establish that BLT mice are permissive for Zika viral infection and are capable of generating viral-specific human immune responses thus providing a human surrogate model for future testing of vaccine and antiviral therapeutic candidates.
Structure-function insights into chikungunya virus capsid protein: Small molecules targeting capsid hydrophobic pocket Virology (IF 3.353) Pub Date : 2018-01-05 Rajesh Sharma, Pooja Kesari, Pravindra Kumar, Shailly Tomar
The crystal structure of chikungunya (CHIKV) virus capsid protease domain has been determined at 2.2 Å. Structure reveals a chymotrypsin-like protease fold with a conserved hydrophobic pocket in CHIKV capsid protein (CP) for interaction with the cytoplasmic tail of E2 (cdE2) similar to the capsid protein of other alphaviruses. Molecular contacts between CP-cdE2 were determined by fitting structures of CHIKV CP and cdE2 into the cryo-EM map of Venezuelan equine encephalitis virus (VEEV). Binding of (S)-(+)-Mandelic acid (MDA) and Ethyl 3-aminobenzoate (EAB) to the hydrophobic pocket of CP was evaluated by molecular docking. Surface plasmon resonance (SPR) and fluorescence spectroscopy experiments confirmed MDA and EAB binding to the CP. The binding constants (KD) obtained from SPR for MDA and EAB were 1.2 × 10−3 M and 0.2 × 10−9 M, respectively. This study adds to the understanding of chikungunya virus structural proteins and may serve as the basis for antiviral development against chikungunya disease.
Phage T4 endonuclease SegD that is similar to group I intron endonucleases does not initiate homing of its own gene Virology (IF 3.353) Pub Date : 2018-01-03 Andrey S. Sokolov, Oleg R. Latypov, Peter M. Kolosov, Michael G. Shlyapnikov, Tamara A. Bezlepkina, Natalia S. Kholod, Farid A. Kadyrov, Igor E. Granovsky
Homing endonucleases are a group of site-specific endonucleases that initiate homing, a nonreciprocal transfer of its own gene into a new allele lacking this gene. This work describes a novel phage T4 endonuclease, SegD, which is homologous to the GIY-YIG family of homing endonucleases. Like other T4 homing endonucleases SegD recognizes an extended, 16 bp long, site, cleaves it asymmetrically to form 3′-protruding ends and digests both unmodified DNA and modified T-even phage DNA with similar efficiencies. Surprisingly, we revealed that SegD cleavage site was identical in the genomes of segD– and segD+ phages. We found that segD gene was expressed during the T4 developmental cycle. Nevertheless, endonuclease SegD was not able to initiate homing of its own gene as well as genetic recombination between phages in its site inserted into the rII locus.
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