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  • Manipulation of Jasmonate Signaling by Plant Viruses and Their Insect Vectors
    Viruses (IF 3.811) Pub Date : 2020-01-27
    Xiujuan Wu; Jian Ye

    Plant viruses pose serious threats to stable crop yield. The majority of them are transmitted by insects, which cause secondary damage to the plant host from the herbivore-vector’s infestation. What is worse, a successful plant virus evolves multiple strategies to manipulate host defenses to promote the population of the insect vector and thereby furthers the disease pandemic. Jasmonate (JA) and its derivatives (JAs) are lipid-based phytohormones with similar structures to animal prostaglandins, conferring plant defenses against various biotic and abiotic challenges, especially pathogens and herbivores. For survival, plant viruses and herbivores have evolved strategies to convergently target JA signaling. Here, we review the roles of JA signaling in the tripartite interactions among plant, virus, and insect vectors, with a focus on the molecular and biochemical mechanisms that drive vector-borne plant viral diseases. This knowledge is essential for the further design and development of effective strategies to protect viral damages, thereby increasing crop yield and food security.

    更新日期:2020-01-27
  • Entomological Assessment of the Status and Risk of Mosquito-borne Arboviral Transmission in Ghana
    Viruses (IF 3.811) Pub Date : 2020-01-27
    Michael Amoa-Bosompem; Daisuke Kobayashi; Katsunori Murota; Astri Nur Faizah; Kentaro Itokawa; Ryosuke Fujita; Joseph Harold Nyarko Osei; Esinam Agbosu; Deborah Pratt; Shohei Kimura; Kofi Dadzie Kwofie; Mitsuko Ohashi; Joseph H. Kofi Bonney; Samuel Dadzie; Toshinori Sasaki; Nobuo Ohta; Haruhiko Isawa; Kyoko Sawabe; Shiroh Iwanaga

    Entomological surveillance is one of the tools used in monitoring and controlling vector-borne diseases. However, the use of entomological surveillance for arboviral infection vector control is often dependent on finding infected individuals. Although this method may suffice in highly endemic areas, it is not as effective in controlling the spread of diseases in low endemic and non-endemic areas. In this study, we examined the efficiency of using entomological markers to assess the status and risk of arbovirus infection in Ghana, which is considered a non-endemic country, by combining mosquito surveillance with virus isolation and detection. This study reports the presence of cryptic species of mosquitoes in Ghana, demonstrating the need to combine morphological identification and molecular techniques in mosquito surveillance. Furthermore, although no medically important viruses were detected, the importance of insect-specific viruses in understanding virus evolution and arbovirus transmission is discussed. This study reports the first mutualistic relationship between dengue virus and the double-stranded RNA Aedes aegypti totivirus. Finally, this study discusses the complexity of the virome of Aedes and Culex mosquitoes and its implication for arbovirus transmission.

    更新日期:2020-01-27
  • Impact of Mutations in Arabidopsis thaliana Metabolic Pathways on Polerovirus Accumulation, Aphid Performance, and Feeding Behavior
    Viruses (IF 3.811) Pub Date : 2020-01-27
    Florent Bogaert; Aurélie Marmonier; Elodie Pichon; Sylvaine Boissinot; Véronique Ziegler-Graff; Quentin Chesnais; Claire Villeroy; Martin Drucker; Véronique Brault

    During the process of virus acquisition by aphids, plants respond to both the virus and the aphids by mobilizing different metabolic pathways. It is conceivable that the plant metabolic responses to both aggressors may be conducive to virus acquisition. To address this question, we analyze the accumulation of the phloem-limited polerovirus Turnip yellows virus (TuYV), which is strictly transmitted by aphids, and aphid’s life traits in six Arabidopsis thaliana mutants (xth33, ss3-2, nata1, myc234, quad, atr1D, and pad4-1). We observed that mutations affecting the carbohydrate metabolism, the synthesis of a non-protein amino acid and the glucosinolate pathway had an effect on TuYV accumulation. However, the virus titer did not correlate with the virus transmission efficiency. Some mutations in A. thaliana affect the aphid feeding behavior but often only in infected plants. The duration of the phloem sap ingestion phase, together with the time preceding the first sap ingestion, affect the virus transmission rate more than the virus titer did. Our results also show that the aphids reared on infected mutant plants had a reduced biomass regardless of the mutation and the duration of the sap ingestion phase.

    更新日期:2020-01-27
  • Phylodynamic Analysis Complements Partner Services by Identifying Acute and Unreported HIV Transmission
    Viruses (IF 3.811) Pub Date : 2020-01-27
    Ellsworth M. Campbell; Anne Patala; Anupama Shankar; Jin-Fen Li; Jeffrey A. Johnson; Emily Westheimer; Cynthia L. Gay; Stephanie E. Cohen; William M. Switzer; Philip J. Peters

    Tailoring public health responses to growing HIV transmission clusters depends on accurately mapping the risk network through which it spreads and identifying acute infections that represent the leading edge of cluster growth. HIV transmission links, especially those involving persons with acute HIV infection (AHI), can be difficult to uncover, or confirm during partner services investigations. We integrated molecular, epidemiologic, serologic and behavioral data to infer and evaluate transmission linkages between participants of a prospective study of AHI conducted in North Carolina, New York City and San Francisco from 2011–2013. Among the 547 participants with newly diagnosed HIV with polymerase sequences, 465 sex partners were reported, of whom only 35 (7.5%) had HIV sequences. Among these 35 contacts, 23 (65.7%) links were genetically supported and 12 (34.3%) were not. Only five links were reported between participants with AHI but none were genetically supported. In contrast, phylodynamic inference identified 102 unreported transmission links, including 12 between persons with AHI. Importantly, all putative transmission links between persons with AHI were found among large clusters with more than five members. Taken together, the presence of putative links between acute participants who did not name each other as contacts that are found only among large clusters underscores the potential for unobserved or undiagnosed intermediaries. Phylodynamics identified many more links than partner services alone and, if routinely and rapidly integrated, can illuminate transmission patterns not readily captured by partner services investigations.

    更新日期:2020-01-27
  • RNA Viruses of Amblyomma variegatum and Rhipicephalus microplus and Cattle Susceptibility in the French Antilles
    Viruses (IF 3.811) Pub Date : 2020-01-26
    Mathilde Gondard; Sarah Temmam; Elodie Devillers; Valérie Pinarello; Thomas Bigot; Delphine Chrétien; Rosalie Aprelon; Muriel Vayssier-Taussat; Emmanuel Albina; Marc Eloit; Sara Moutailler

    Ticks transmit a wide variety of pathogens including bacteria, parasites and viruses. Over the last decade, numerous novel viruses have been described in arthropods, including ticks, and their characterization has provided new insights into RNA virus diversity and evolution. However, little is known about their ability to infect vertebrates. As very few studies have described the diversity of viruses present in ticks from the Caribbean, we implemented an RNA-sequencing approach on Amblyomma variegatum and Rhipicephalus microplus ticks collected from cattle in Guadeloupe and Martinique. Among the viral communities infecting Caribbean ticks, we selected four viruses belonging to the Chuviridae, Phenuiviridae and Flaviviridae families for further characterization and designing antibody screening tests. While viral prevalence in individual tick samples revealed high infection rates, suggesting a high level of exposure of Caribbean cattle to these viruses, no seropositive animals were detected. These results suggest that the Chuviridae- and Phenuiviridae-related viruses identified in the present study are more likely tick endosymbionts, raising the question of the epidemiological significance of their occurrence in ticks, especially regarding their possible impact on tick biology and vector capacity. The characterization of these viruses might open the door to new ways of preventing and controlling tick-borne diseases.

    更新日期:2020-01-26
  • Virus Discovery in Desert Tortoise Fecal Samples: Novel Circular Single-Stranded DNA Viruses
    Viruses (IF 3.811) Pub Date : 2020-01-26
    Joseph P. Orton; Matheo Morales; Rafaela S. Fontenele; Kara Schmidlin; Simona Kraberger; Daniel J. Leavitt; Timothy H. Webster; Melissa A. Wilson; Kenro Kusumi; Greer A. Dolby; Arvind Varsani

    The Sonoran Desert tortoise Gopherus morafkai is adapted to the desert, and plays an important ecological role in this environment. There is limited information on the viral diversity associated with tortoises (family Testudinidae), and to date no DNA virus has been identified associated with these animals. This study aimed to assess the diversity of DNA viruses associated with the Sonoran Desert tortoise by sampling their fecal matter. A viral metagenomics approach was used to identify the DNA viruses in fecal samples from wild Sonoran Desert tortoises in Arizona, USA. In total, 156 novel single-stranded DNA viruses were identified from 40 fecal samples. Those belonged to two known viral families, the Genomoviridae (n = 27) and Microviridae (n = 119). In addition, 10 genomes were recovered that belong to the unclassified group of circular-replication associated protein encoding single-stranded (CRESS) DNA virus and five circular molecules encoding viral-like proteins.

    更新日期:2020-01-26
  • Characterization of Molecular Cluster Detection and Evaluation of Cluster Investigation Criteria Using Machine Learning Methods and Statewide Surveillance Data in Washington State
    Viruses (IF 3.811) Pub Date : 2020-01-26
    Steven J. Erly; Joshua T. Herbeck; Roxanne P. Kerani; Jennifer R. Reuer

    Molecular cluster detection can be used to interrupt HIV transmission but is dependent on identifying clusters where transmission is likely. We characterized molecular cluster detection in Washington State, evaluated the current cluster investigation criteria, and developed a criterion using machine learning. The population living with HIV (PLWH) in Washington State, those with an analyzable genotype sequences, and those in clusters were described across demographic characteristics from 2015 to2018. The relationship between 3- and 12-month cluster growth and demographic, clinical, and temporal predictors were described, and a random forest model was fit using data from 2016 to 2017. The ability of this model to identify clusters with future transmission was compared to Centers for Disease Control and Prevention (CDC) and the Washington state criteria in 2018. The population with a genotype was similar to all PLWH, but people in a cluster were disproportionately white, male, and men who have sex with men. The clusters selected for investigation by the random forest model grew on average 2.3 cases (95% CI 1.1–1.4) in 3 months, which was not significantly larger than the CDC criteria (2.0 cases, 95% CI 0.5–3.4). Disparities in the cases analyzed suggest that molecular cluster detection may not benefit all populations. Jurisdictions should use auxiliary data sources for prediction or continue using established investigation criteria.

    更新日期:2020-01-26
  • Understanding the Evolutionary Ecology of host--pathogen Interactions Provides Insights into the Outcomes of Insect Pest Biocontrol
    Viruses (IF 3.811) Pub Date : 2020-01-25
    David Paez; Arietta Fleming-Davies

    The use of viral pathogens to control thepopulation size of pest insects has produced both successful and unsuccessful outcomes. Here, we investigate whether those biocontrol successes and failures can be explained by key ecological and evolutionary processes between hosts and pathogens. Specifically, we examine how heterogeneity inpathogen transmission, ecological and evolutionary tradeoffs, andpathogen diversity affect insect population density and thus successful control. Wefirst review theexisting literature and then use numerical simulations of mathematical models to further explore these processes. Our results show that thecontrol of insect densities using viruses depends strongly on theheterogeneity of virus transmission among insects. Overall, increased heterogeneity of transmission reduces theeffect of viruses on insect densities and increases thelong-term stability of insect populations. Lower equilibrium insect densities occur when transmission is heritable and when there is atradeoff between mean transmission and insect fecundity compared to when theheterogeneity of transmission arises from non-genetic sources. Thus, theheterogeneity of transmission is akey parameter that regulates thelong-term population dynamics of insects and their pathogens. Wealso show that both heterogeneity of transmission and life-history tradeoffs modulate characteristics of population dynamics such as thefrequency and intensity of ``boom--bust" population cycles. Furthermore, we show that because of life-history tradeoffs affecting thetransmission rate, theuse of multiple pathogen strains is more effective than theuse of asingle strain to control insect densities only when thepathogen strains differ considerably intheir transmission characteristics. By quantifying theeffects of ecology and evolution on population densities, we are able to offer recommendations to assess thelong-term effects of classical biocontrol.

    更新日期:2020-01-26
  • Dynamic Shifts in the HIV Proviral Landscape During Long Term Combination Antiretroviral Therapy: Implications for Persistence and Control of HIV Infections
    Viruses (IF 3.811) Pub Date : 2020-01-25
    Elizabeth M. Anderson; Francesco R. Simonetti; Robert J. Gorelick; Shawn Hill; Monica A. Gouzoulis; Jennifer Bell; Catherine Rehm; Liliana Pérez; Eli Boritz; Xiaolin Wu; Daria Wells; Stephen H. Hughes; Venigalla Rao; John M. Coffin; Mary F. Kearney; Frank Maldarelli

    Combination antiretroviral therapy (cART) controls but does not eradicate HIV infection; HIV persistence is the principal obstacle to curing infections. The proportion of defective proviruses increases during cART, but the dynamics of this process are not well understood, and a quantitative analysis of how the proviral landscape is reshaped after cART is initiated is critical to understanding how HIV persists. Here, we studied longitudinal samples from HIV infected individuals undergoing long term cART using multiplexed Droplet Digital PCR (ddPCR) approaches to quantify the proportion of deleted proviruses in lymphocytes. In most individuals undergoing cART, HIV proviruses that contain gag are lost more quickly than those that lack gag. Increases in the fraction of gag-deleted proviruses occurred only after 1–2 years of therapy, suggesting that the immune system, and/or toxicity of viral re-activation helps to gradually shape the proviral landscape. After 10–15 years on therapy, there were as many as 3.5–5 times more proviruses in which gag was deleted or highly defective than those containing intact gag. We developed a provirus-specific ddPCR approach to quantify individual clones. Investigation of a clone of cells containing a deleted HIV provirus integrated in the HORMAD2 gene revealed that the cells underwent a massive expansion shortly after cART was initiated until the clone, which was primarily in effector memory cells, dominated the population of proviruses for over 6 years. The expansion of this HIV-infected clone had substantial effects on the overall proviral population.

    更新日期:2020-01-26
  • SV40 Large T Antigen Is Not Responsible for the Loss of STING in 293T Cells but Can Inhibit cGAS-STING Interferon Induction
    Viruses (IF 3.811) Pub Date : 2020-01-24
    Joshua B. Reus; Guillermo S. Trivino-Soto; Lily I. Wu; Kristiana Kokott; Efrem S. Lim

    Several DNA viruses have evolved antagonists to inhibit the cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING) DNA-sensing immune pathway. This includes DNA viral oncogenes that antagonize the cGAS-STING pathway by binding STING through the LxCxE motif. The 293T human cells are widely used in biology studies as they are highly transfectable. While parental 293 cells express high levels of STING, 293T cells lack STING and are unable to induce interferon antiviral responses to cytosolic DNA. Additionally, 293T cells express the SV40 polyomavirus large T antigen (LT) which enhances the replication of transfected DNA plasmids carrying the SV40 origin of replication. Since SV40 LT also encodes the LxCxE motif, the lack of STING expression in 293T cells is commonly assumed to be due to SV40 large T antigen. We find that SV40 LT does not alter exogenously expressed and endogenous levels of STING protein. We show that STING transcription is suppressed in 293T cells but is not driven by SV40. This study also revealed that SV40 LT does indeed inhibit cGAS-STING interferon induction, but through a mechanism distinct from other DNA virus oncogenes. Collectively, these results indicate that while SV40 LT can inhibit cGAS-STING interferon induction, it does so in an unanticipated manner.

    更新日期:2020-01-24
  • Presence of Flavivirus Antibodies Does Not Lead to a Greater Number of Symptoms in a Small Cohort of Canadian Travelers Infected with Zika Virus
    Viruses (IF 3.811) Pub Date : 2020-01-24
    Robert A. Kozak; Lee W. Goneau; Cedric DeLima; Olivia Varsaneux; AliReza Eshaghi; Erik Kristjanson; Romy Olsha; David Safronetz; Stephen Perusini; Christine Frantz; Jonathan B. Gubbay

    Zika virus (ZIKV) is a mosquito-borne flavivirus associated with a febrile illness as well as severe complications, including microcephaly and Guillain-Barré Syndrome. Antibody cross-reactivity between flaviviruses has been documented, and in regions where ZIKV is circulating, dengue virus (DENV) is also endemic, leaving the potential that previous exposure to DENV could alter clinical features of ZIKV infection. To investigate this, we performed a retrospective case-control study in which we compared Canadian travellers who had been infected with ZIKV and had serological findings indicating previous DENV or other flavivirus exposure (n = 16) to those without any previous exposure (n = 44). Patient samples were collected between February 2016 and September 2017 and submitted to Public Health Ontario for testing. ZIKV infection was determined using real-time RT-PCR and antibodies against DENV were identified by the plaque-reduction neutralization test. The mean time from symptom onset to sample collection was 5 days for both groups; the magnitude of viremia was not statistically different (Ct values: 35.6 vs. 34.9, p-value = 0.2). Clinical scores were also similar. Our findings indicate that previous DENV or other flavivirus exposure did not result in greater viremia or a higher illness score.

    更新日期:2020-01-24
  • Optimized Hepatitis E Virus (HEV) Culture and its Application to Measurements of HEV Infectivity
    Viruses (IF 3.811) Pub Date : 2020-01-24
    Nicolas Capelli; Martine Dubois; Mélanie Pucelle; Isabelle Da Silva; Sébastien Lhomme; Florence Abravanel; Sabine Chapuy-Regaud; Jacques Izopet

    Hepatitis E virus (HEV) is a major concern in public health worldwide. Infections with HEV genotypes 3, 4, or 7 can lead to chronic hepatitis while genotype 1 infections can trigger severe hepatitis in pregnant women. Infections with all genotypes can worsen chronic liver diseases. As virions are lipid-associated in blood and naked in feces, efficient methods of propagating HEV clinical strains in vitro and evaluating the infectivity of both HEV forms are needed. We evaluated the spread of clinical strains of HEV genotypes 1 (HEV1) and 3 (HEV3) by quantifying viral RNA in culture supernatants and cell lysates. Infectivity was determined by endpoint dilution and calculation of the tissue culture infectious dose 50 (TCID50). An enhanced HEV production could be obtained varying the composition of the medium, including fetal bovine serum (FBS) and dimethylsulfoxide (DMSO) content. This increased TCID50 from 10 to 100-fold and allowed us to quantify HEV1 infectivity. These optimized methods for propagating and measuring HEV infectivity could be applied to health safety processes and will be useful for testing new antiviral drugs.

    更新日期:2020-01-24
  • Smallpox in the Post-Eradication Era
    Viruses (IF 3.811) Pub Date : 2020-01-24
    Hermann Meyer; Rosina Ehmann; Geoffrey L. Smith

    Widespread vaccination programmes led to the global eradication of smallpox, which was certified by the World Health Organisation (WHO), and, since 1978, there has been no case of smallpox anywhere in the world. However, the viable variola virus (VARV), the causative agent of smallpox, is still kept in two maximum security laboratories in Russia and the USA. Despite the eradication of the disease smallpox, clandestine stocks of VARV may exist. In a rapidly changing world, the impact of an intentional VARV release in the human population would nowadays result in a public health emergency of global concern: vaccination programmes were abolished, the percentage of immunosuppressed individuals in the human population is higher, and an increased intercontinental air travel allows for the rapid viral spread of diseases around the world. The WHO has authorised the temporary retention of VARV to enable essential research for public health benefit to take place. This work aims to develop diagnostic tests, antiviral drugs, and safer vaccines. Advances in synthetic biology have made it possible to produce infectious poxvirus particles from chemicals in vitro so that it is now possible to reconstruct VARV. The status of smallpox in the post-eradication era is reviewed.

    更新日期:2020-01-24
  • Return of the Coronavirus: 2019-nCoV
    Viruses (IF 3.811) Pub Date : 2020-01-24
    Lisa E. Gralinski; Vineet D. Menachery

    The emergence of a novel coronavirus (2019-nCoV) has awakened the echoes of SARS-CoV from nearly two decades ago. Yet, with technological advances and important lessons gained from previous outbreaks, perhaps the world is better equipped to deal with the most recent emergent group 2B coronavirus.

    更新日期:2020-01-24
  • Molecular Detection of Rabies Lyssaviruses from Dogs in Southeastern Nigeria: Evidence of TransboundaryTransmission of Rabies in West Africa
    Viruses (IF 3.811) Pub Date : 2020-01-23
    Ukamaka U Eze; Ernest C Ngoepe; Boniface M Anene; Romanus C Ezeokonkwo; Chika I Nwosuh; Claude T Sabeta

    Despite being the first country to register confirmed cases of Mokola and Lagos bat lyssaviruses (two very distant lyssaviruses), knowledge gaps, particularly on the molecular epidemiology of lyssaviruses, still exist in Nigeria. A total of 278 specimens were collected from dogs in southeastern Nigeria between October 2015 and July 2016, and 23 (8.3%) of these tested positive for lyssaviruses with the direct fluorescent antibody test (DFA). The lyssaviruses were genetically characterized by amplifying the highly conserved nucleoprotein (N) gene of the rabies lyssaviruses (RABVs) of the viral genome. Phylogenetic analyses of the nucleotide sequences showed that all the RABV sequences in this study were of the Africa-2 lineage. Our results demonstrated that transboundary transmission of rabies lyssavirus is a key event, given that one of the RABV sequences (MN196576) clustered with rabies variants from neighboring Niger Republic. Furthermore, three RABVs from dogs from Anambra State clustered separately forming a novel and distinct group. Our results demonstrated that transboundary transmission of RABLVs is a key driver in the spread of rabies in West Africa. In order for the successful control of this zoonotic disease, a multinational stepwise surveillance and elimination of rabies in Africa by 2030 is probably the solution for regional elimination.

    更新日期:2020-01-23
  • Bioprospecting Staphylococcus Phages with Therapeutic and Bio-Control Potential
    Viruses (IF 3.811) Pub Date : 2020-01-23
    Joseph M. Ochieng’ Oduor; Ermir Kadija; Atunga Nyachieo; Marianne W. Mureithi; Mikael Skurnik

    Emergence of antibiotic-resistant bacteria is a serious threat to the public health. This is also true for Staphylococcus aureus and other staphylococci. Staphylococcus phages Stab20, Stab21, Stab22, and Stab23, were isolated in Albania. Based on genomic and phylogenetic analysis, they were classified to genus Kayvirus of the subfamily Twortvirinae. In this work, we describe the in-depth characterization of the phages that electron microscopy confirmed to be myoviruses. These phages showed tolerance to pH range of 5.4 to 9.4, to maximum UV radiation energy of 25 µJ/cm2, to temperatures up to 45 °C, and to ethanol concentrations up to 25%, and complete resistance to chloroform. The adsorption rate constants of the phages ranged between 1.0 × 10−9 mL/min and 4.7 × 10−9 mL/min, and the burst size was from 42 to 130 plaque-forming units. The phages Stab20, 21, 22, and 23, originally isolated using Staphylococcus xylosus as a host, demonstrated varied host ranges among different Staphylococcus strains suggesting that they could be included in cocktail formulations for therapeutic or bio-control purpose. Phage particle proteomes, consisting on average of ca 60–70 gene products, revealed, in addition to straight-forward structural proteins, also the presence of enzymes such DNA polymerase, helicases, recombinases, exonucleases, and RNA ligase polymer. They are likely to be injected into the bacteria along with the genomic DNA to take over the host metabolism as soon as possible after infection.

    更新日期:2020-01-23
  • The Potyviruses: An Evolutionary Synthesis Is Emerging
    Viruses (IF 3.811) Pub Date : 2020-01-22
    Adrian J. Gibbs; Mohammad Hajizadeh; Kazusato Ohshima; Roger A.C. Jones

    In this review, encouraged by the dictum of Theodosius Dobzhansky that “Nothing in biology makes sense except in the light of evolution”, we outline the likely evolutionary pathways that have resulted in the observed similarities and differences of the extant molecules, biology, distribution, etc. of the potyvirids and, especially, its largest genus, the potyviruses. The potyvirids are a family of plant-infecting RNA-genome viruses. They had a single polyphyletic origin, and all share at least three of their genes (i.e., the helicase region of their CI protein, the RdRp region of their NIb protein and their coat protein) with other viruses which are otherwise unrelated. Potyvirids fall into 11 genera of which the potyviruses, the largest, include more than 150 distinct viruses found worldwide. The first potyvirus probably originated 15,000–30,000 years ago, in a Eurasian grass host, by acquiring crucial changes to its coat protein and HC-Pro protein, which enabled it to be transmitted by migrating host-seeking aphids. All potyviruses are aphid-borne and, in nature, infect discreet sets of monocotyledonous or eudicotyledonous angiosperms. All potyvirus genomes are under negative selection; the HC-Pro, CP, Nia, and NIb genes are most strongly selected, and the PIPO gene least, but there are overriding virus specific differences; for example, all turnip mosaic virus genes are more strongly conserved than those of potato virus Y. Estimates of dN/dS (ω) indicate whether potyvirus populations have been evolving as one or more subpopulations and could be used to help define species boundaries. Recombinants are common in many potyvirus populations (20%–64% in five examined), but recombination seems to be an uncommon speciation mechanism as, of 149 distinct potyviruses, only two were clear recombinants. Human activities, especially trade and farming, have fostered and spread both potyviruses and their aphid vectors throughout the world, especially over the past five centuries. The world distribution of potyviruses, especially those found on islands, indicates that potyviruses may be more frequently or effectively transmitted by seed than experimental tests suggest. Only two meta-genomic potyviruses have been recorded from animal samples, and both are probably contaminants.

    更新日期:2020-01-23
  • TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Vesicular Stomatitis Virus Infection
    Viruses (IF 3.811) Pub Date : 2020-01-22
    Girish Patil; Lingling Xu; Yakun Wu; Kun Song; Wenzhuo Hao; Fang Hua; Lingyan Wang; Shitao Li

    Vesicular stomatitis virus (VSV) is a zoonotic, negative-stranded RNA virus of the family Rhabdoviridae. The nucleoprotein (N) of VSV protects the viral genomic RNA and plays an essential role in viral transcription and replication, which makes the nucleoprotein an ideal target of host defense. However, whether and how host innate/intrinsic immunity limits VSV infection by targeting the N protein are unknown. In this study, we found that the N protein of VSV (VSV-N) interacted with a ubiquitin E3 ligase, tripartite motif protein 41 (TRIM41). Overexpression of TRIM41 inhibited VSV infection. Conversely, the depletion of TRIM41 increased host susceptibility to VSV. Furthermore, the E3 ligase defective mutant of TRIM41 failed to limit VSV infection, suggesting the requirement of the E3 ligase activity of TRIM41 in viral restriction. Indeed, TRIM41 ubiquitinated VSV-N in cells and in vitro. TRIM41-mediated ubiquitination leads to the degradation of VSV-N through proteasome, thereby limiting VSV infection. Taken together, our study identifies TRIM41 as a new intrinsic immune factor against VSV by targeting the viral nucleoprotein for ubiquitination and subsequent protein degradation.

    更新日期:2020-01-23
  • Emerging Viruses without Borders: The Wuhan Coronavirus
    Viruses (IF 3.811) Pub Date : 2020-01-22
    Shan-Lu Liu; Linda Saif

    The recently emerged coronavirus in Wuhan, China has claimed at least two lives as of January 17 and infected hundreds if not thousands of individuals. The situation has drawn international attention, including from the virology community. We applaud the rapid release to the public of the genome sequence of the new virus by Chinese virologists, but we also believe that increased transparency on disease reporting and data sharing with international colleagues are crucial for curbing the spread of this newly emerging virus to other parts of the world.

    更新日期:2020-01-23
  • Defenses against Virus and Vector: A Phloem-Biological Perspective on RTM- and SLI1-Mediated Resistance to Potyviruses and Aphids
    Viruses (IF 3.811) Pub Date : 2020-01-22
    Karen J. Kloth; Richard Kormelink

    Combining plant resistance against virus and vector presents an attractive approach to reduce virus transmission and virus proliferation in crops. Restricted Tobacco-etch virus Movement (RTM) genes confer resistance to potyviruses by limiting their long-distance transport. Recently, a close homologue of one of the RTM genes, SLI1, has been discovered but this gene instead confers resistance to Myzus persicae aphids, a vector of potyviruses. The functional connection between resistance to potyviruses and aphids, raises the question whether plants have a basic defense system in the phloem against biotic intruders. This paper provides an overview on restricted potyvirus phloem transport and restricted aphid phloem feeding and their possible interplay, followed by a discussion on various ways in which viruses and aphids gain access to the phloem sap. From a phloem-biological perspective, hypotheses are proposed on the underlying mechanisms of RTM- and SLI1-mediated resistance, and their possible efficacy to defend against systemic viruses and phloem-feeding vectors.

    更新日期:2020-01-23
  • Risk Mapping of Influenza D Virus Occurrence in Ruminants and Swine in Togo Using a Spatial Multicriteria Decision Analysis Approach
    Viruses (IF 3.811) Pub Date : 2020-01-21
    Maxime Fusade-Boyer; Pidemnéwé S. Pato; Mathias Komlan; Koffi Dogno; Komla Batawui; Emilie Go-Maro; Pamela McKenzie; Claire Guinat; Aurélie Secula; Mathilde Paul; Richard J. Webby; Annelise Tran; Agnès Waret-Szkuta; Mariette F. Ducatez

    Influenza D virus (IDV) has been identified in several continents, with serological evidence for the virus in Africa. In order to improve the sensitivity and cost–benefit of IDV surveillance in Togo, risk maps were drawn using a spatial multicriteria decision analysis (MCDA) and experts’ opinion to evaluate the relevance of sampling areas used so far. Areas at highest risk of IDV occurrence were the main cattle markets. The maps were evaluated with previous field surveillance data collected in Togo between 2017 and 2019: 1216 sera from cattle, small ruminants, and swine were screened for antibodies to IDV by hemagglutination inhibition (HI) assays. While further samples collections are needed to validate the maps, the risk maps resulting from the spatial MCDA approach generated here highlight several priority areas for IDV circulation assessment.

    更新日期:2020-01-22
  • The Impact of Cellular Proliferation on the HIV-1 Reservoir
    Viruses (IF 3.811) Pub Date : 2020-01-21
    Maria C. Virgilio; Kathleen L. Collins

    Human immunodeficiency virus (HIV) is a chronic infection that destroys the immune system in infected individuals. Although antiretroviral therapy is effective at preventing infection of new cells, it is not curative. The inability to clear infection is due to the presence of a rare, but long-lasting latent cellular reservoir. These cells harboring silent integrated proviral genomes have the potential to become activated at any moment, making therapy necessary for life. Latently-infected cells can also proliferate and expand the viral reservoir through several methods including homeostatic proliferation and differentiation. The chromosomal location of HIV proviruses within cells influences the survival and proliferative potential of host cells. Proliferating, latently-infected cells can harbor proviruses that are both replication-competent and defective. Replication-competent proviral genomes contribute to viral rebound in an infected individual. The majority of available techniques can only assess the integration site or the proviral genome, but not both, preventing reliable evaluation of HIV reservoirs.

    更新日期:2020-01-22
  • Hepatitis B Virus (HBV) Subviral Particles as Protective Vaccines and Vaccine Platforms
    Viruses (IF 3.811) Pub Date : 2020-01-21
    Joan Kha-Tu Ho; Beena Jeevan-Raj; Hans-Jürgen Netter

    : Hepatitis B remains one of the major global health problems more than 40 years after the identification of human hepatitis B virus (HBV) as the causative agent. A critical turning point in combating this virus was the development of a preventative vaccine composed of the HBV surface (envelope) protein (HBsAg) to reduce the risk of new infections. The isolation of HBsAg sub-viral particles (SVPs) from the blood of asymptomatic HBV carriers as antigens for the first-generation vaccines, followed by the development of recombinant HBsAg SVPs produced in yeast as the antigenic components of the second-generation vaccines, represent landmark advancements in biotechnology and medicine. The ability of the HBsAg SVPs to accept and present foreign antigenic sequences provides the basis of a chimeric particulate delivery platform, and resulted in the development of a vaccine against malaria (RTS,S/AS01, MosquirixTM), and various preclinical vaccine candidates to overcome infectious diseases for which there are no effective vaccines. Biomedical modifications of the HBsAg subunits allowed the identification of strategies to enhance the HBsAg SVP immunogenicity to build potent vaccines for preventative and possibly therapeutic applications. The review provides an overview of the formation and assembly of the HBsAg SVPs and highlights the utilization of the particles in key effective vaccines.

    更新日期:2020-01-22
  • Characterization of the Immune Response of MERS-CoV Vaccine Candidates Derived from Two Different Vectors in Mice
    Viruses (IF 3.811) Pub Date : 2020-01-20
    Entao Li; Feihu Yan; Pei Huang; Hang Chi; Shengnan Xu; Guohua Li; Chuanyu Liu; Na Feng; Hualei Wang; Yongkun Zhao; Songtao Yang; Xianzhu Xia

    Middle East respiratory syndrome (MERS) is an acute, high-mortality-rate, severe infectious disease caused by an emerging MERS coronavirus (MERS-CoV) that causes severe respiratory diseases. The continuous spread and great pandemic potential of MERS-CoV make it necessarily important to develop effective vaccines. We previously demonstrated that the application of Gram-positive enhancer matrix (GEM) particles as a bacterial vector displaying the MERS-CoV receptor-binding domain (RBD) is a very promising MERS vaccine candidate that is capable of producing potential neutralization antibodies. We have also used the rabies virus (RV) as a viral vector to design a recombinant vaccine by expressing the MERS-CoV S1 (spike) protein on the surface of the RV. In this study, we compared the immunological efficacy of the vaccine candidates in BALB/c mice in terms of the levels of humoral and cellular immune responses. The results show that the rabies virus vector-based vaccine can induce remarkably earlier antibody response and higher levels of cellular immunity than the GEM particles vector. However, the GEM particles vector-based vaccine candidate can induce remarkably higher antibody response, even at a very low dose of 1 µg. These results indicate that vaccines constructed using different vaccine vector platforms for the same pathogen have different rates and trends in humoral and cellular immune responses in the same animal model. This discovery not only provides more alternative vaccine development platforms for MERS-CoV vaccine development, but also provides a theoretical basis for our future selection of vaccine vector platforms for other specific pathogens.

    更新日期:2020-01-21
  • Identification of A Novel Papillomavirus Associated with Squamous Cell Carcinoma in A Domestic Cat
    Viruses (IF 3.811) Pub Date : 2020-01-20
    Maura Carrai; Kate Van Brussel; Mang Shi; Ci-Xiu Li; Wei-Shan Chang; John S. Munday; Katja Voss; Alicia McLuckie; David Taylor; Andrew Laws; Edward C. Holmes; Vanessa R. Barrs; Julia A. Beatty

    Papillomaviruses infect the skin and mucosal surfaces of diverse animal hosts with consequences ranging from asymptomatic colonization to highly malignant epithelial cancers. Increasing evidence suggests a role for papillomaviruses in the most common cutaneous malignancy of domestic cats, squamous cell carcinoma (SCC). Using total DNA sequencing we identified a novel feline papillomavirus in a nasal biopsy taken from a cat presenting with both nasal cavity lymphoma and recurrent squamous cell carcinoma affecting the nasal planum. We designate this novel virus as Felis catus papillomavirus 6 (FcaPV6). The complete FcaPV6 7453 bp genome was similar to those of other feline papillomaviruses and phylogenetic analysis revealed that it was most closely related to FcaPV3, although was distinct enough to represent a new viral type. Classification of FcaPV6 in a new genus alongside FcaPVs 3, 4 and 5 is supported. Archived excisional biopsy of the SCC, taken 20 months prior to presentation, was intensely positive on p16 immunostaining. FcaPV6, amplified using virus-specific, but not consensus, PCR, was the only papillomavirus detected in DNA extracted from the SCC. Conversely, renal lymphoma, sampled at necropsy two months after presentation, tested negative on FcaPV6-specific PCR. In sum, using metagenomics we demonstrate the presence of a novel feline papillomavirus in association with cutaneous squamous cell carcinoma.

    更新日期:2020-01-21
  • Multi-Approach Investigation Regarding the West Nile Virus Situation in Hungary, 2018
    Viruses (IF 3.811) Pub Date : 2020-01-20
    Brigitta Zana; Károly Erdélyi; Anna Nagy; Eszter Mezei; Orsolya Nagy; Mária Takács; Tamás Bakonyi; Petra Forgách; Orsolya Korbacska-Kutasi; Orsolya Fehér; Péter Malik; Krisztina Ursu; Péter Kertész; Anett Kepner; Máté Martina; Tamás Süli; Zsófia Lanszki; Gábor Endre Tóth; Anett Kuczmog; Balázs Somogyi; Ferenc Jakab; Gábor Kemenesi

    The West Nile virus is endemic in multiple European countries and responsible for several epidemics throughout the European region. Its evolution into local or even widespread epidemics is driven by multiple factors from genetic diversification of the virus to environmental conditions. The year of 2018 was characterized by an extraordinary increase in human and animal cases in the Central-Eastern European region, including Hungary. In a collaborative effort, we summarized and analyzed the genetic and serologic data of WNV infections from multiple Hungarian public health institutions, universities, and private organizations. We compared human and veterinary serologic data, along with NS5 and NS3 gene sequence data through 2018. Wild birds were excellent indicator species for WNV circulation in each year. Our efforts resulted in documenting the presence of multiple phylogenetic subclades with Balkans and Western-European progenitor sequences of WNV circulating among human and animal populations in Hungary prior to and during the 2018 epidemic. Supported by our sequence and phylogenetic data, the epidemic of 2018 was not caused by recently introduced WNV strains. Unfortunately, Hungary has no country-wide integrated surveillance system which would enable the analysis of related conditions and provide a comprehensive epidemiological picture. The One Health approach, involving multiple institutions and experts, should be implemented in order to fully understand ecological background factors driving the evolution of future epidemics.

    更新日期:2020-01-21
  • 5,6-Dichloro-2-phenyl-benzotriazoles: New Potent Inhibitors of Orthohantavirus
    Viruses (IF 3.811) Pub Date : 2020-01-20
    Giuseppina Sanna; Sandra Piras; Silvia Madeddu; Bernardetta Busonera; Boris Klempa; Paola Corona; Roberta Ibba; Gabriele Murineddu; Antonio Carta; Roberta Loddo

    Orthohantaviruses, previously known as hantaviruses (family Hantaviridae, order Bunyavirales), are emerging zoonoses hosted by different rodent and insectivore species. Orthohantaviruses are transmitted by aerosolized excreta (urine, saliva and feces) of their reservoir hosts. When transmitted to humans, they cause hemorrhagic fever with renal syndrome (HFRS) in Asia and Europe and hantavirus (cardio) pulmonary syndrome (HPS) in the Americas. Clinical studies have shown that early treatments of HFRS patients with ribavirin (RBV) improve prognosis. Nevertheless, there is the need for urgent development of specific antiviral drugs. In the search for new RNA virus inhibitors, we recently identified a series of variously substituted 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazole derivatives active against the human respiratory syncytial virus (HRSV). Interestingly, several 2-phenyl-benzotriazoles resulted in fairly potent inhibitors of the Hantaan virus in a chemiluminescence focus reduction assay (C-FRA) showing an EC50 = 4–5 µM, ten-fold more active than ribavirin. Currently, there are no FDA approved drugs for the treatment of orthohantavirus infections. Antiviral activities and cytotoxicity profiles suggest that 5,6-dichloro-1(2)-phenyl-1(2)H-benzo[d][1,2,3]triazoles could be promising candidates for further investigation as a potential treatment of hantaviral diseases.

    更新日期:2020-01-21
  • Microtubules in Polyomavirus Infection
    Viruses (IF 3.811) Pub Date : 2020-01-18
    Lenka Horníková; Kateřina Bruštíková; Jitka Forstová

    Microtubules, part of the cytoskeleton, are indispensable for intracellular movement, cell division, and maintaining cell shape and polarity. In addition, microtubules play an important role in viral infection. In this review, we summarize the role of the microtubules’ network during polyomavirus infection. Polyomaviruses usurp microtubules and their motors to travel via early and late acidic endosomes to the endoplasmic reticulum. As shown for SV40, kinesin-1 and microtubules are engaged in the release of partially disassembled virus from the endoplasmic reticulum to the cytosol, and dynein apparently assists in the further disassembly of virions prior to their translocation to the cell nucleus—the place of their replication. Polyomavirus gene products affect the regulation of microtubule dynamics. Early T antigens destabilize microtubules and cause aberrant mitosis. The role of these activities in tumorigenesis has been documented. However, its importance for productive infection remains elusive. On the other hand, in the late phase of infection, the major capsid protein, VP1, of the mouse polyomavirus, counteracts T-antigen-induced destabilization. It physically binds microtubules and stabilizes them. The interaction results in the G2/M block of the cell cycle and prolonged S phase, which is apparently required for successful completion of the viral replication cycle.

    更新日期:2020-01-21
  • Using the LN34 Pan-Lyssavirus Real-Time RT-PCR Assay for Rabies Diagnosis and Rapid Genetic Typing from Formalin-Fixed Human Brain Tissue
    Viruses (IF 3.811) Pub Date : 2020-01-18
    Rene Edgar Condori; Michael Niezgoda; Griselda Lopez; Carmen Acosta Matos; Elinna Diaz Mateo; Crystal Gigante; Claire Hartloge; Altagracia Pereira Filpo; Joseph Haim; Panayampalli Subbian Satheshkumar; Brett Petersen; Ryan Wallace; Victoria Olson; Yu Li

    Human rabies post mortem diagnostic samples are often preserved in formalin. While immunohistochemistry (IHC) has been routinely used for rabies antigen detection in formalin-fixed tissue, the formalin fixation process causes nucleic acid fragmentation that may affect PCR amplification. This study reports the diagnosis of rabies in an individual from the Dominican Republic using both IHC and the LN34 pan-lyssavirus real-time RT-PCR assay on formalin-fixed brain tissue. The LN34 assay generates a 165 bp amplicon and demonstrated higher sensitivity than traditional PCR. Multiple efforts to amplify nucleic acid fragments larger than 300 bp using conventional PCR were unsuccessful, probably due to RNA fragmentation. Sequences generated from the LN34 amplicon linked the case to the rabies virus (RABV) strain circulating in the Ouest Department of Haiti to the border region between Haiti and the Dominican Republic. Direct sequencing of the LN34 amplicon allowed rapid and low-cost rabies genetic typing.

    更新日期:2020-01-21
  • Acknowledgement to Reviewers of Viruses in 2019
    Viruses (IF 3.811) Pub Date : 2020-01-17
    Viruses Editorial Office

    No abstract available

    更新日期:2020-01-17
  • Integrated Analysis of Differentially Expressed miRNAs and mRNAs in Goat Skin Fibroblast Cells in Response to Orf Virus Infection Reveals That cfa-let-7a Regulates Thrombospondin 1 Expression
    Viruses (IF 3.811) Pub Date : 2020-01-17
    Feng Pang; Xinying Wang; Zhen Chen; Zhenxing Zhang; Mengmeng Zhang; Chengqiang Wang; Xiaohong Yang; Qi An; Li Du; Fengyang Wang

    Orf is a zoonotic disease that has caused huge economic losses globally. Systematical analysis of dysregulated cellular micro RNAs (miRNAs) in response to Orf virus (ORFV) infection has not been reported. In the current study, miRNA sequencing and RNA sequencing (RNA-seq) were performed in goat skin fibroblast (GSF) cells at 0, 18, and 30 h post infection (h.p.i). We identified 140 and 221 differentially expressed (DE) miRNAs at 18 and 30 h.p.i, respectively. We also identified 729 and 3961 DE genes (DEGs) at 18 and 30 h.p.i, respectively. GO enrichment analysis indicates enrichment of apoptotic regulation, defense response to virus, immune response, and inflammatory response at both time points. DE miRNAs and DEGs with reverse expression were used to construct miRNA-gene networks. Seven DE miRNAs and seven DEGs related to “negative regulation of viral genome replication” were identified. These were validated by RT-qPCR. Cfa-let-7a, a significantly upregulated miRNA, was found to repress Thrombospondin 1 (THBS1) mRNA and protein expression by directly targeting the THBS1 3′ untranslated region. THBS1 has been reported to induce apoptosis; therefore, the cfa-let-7a-THBS1 axis may play an important role in cellular apoptosis during ORFV infection. This study provides new insights into ORFV and host cell interaction mechanisms.

    更新日期:2020-01-17
  • Microtubules in Influenza Virus Entry and Egress
    Viruses (IF 3.811) Pub Date : 2020-01-17
    Caitlin Simpson; Yohei Yamauchi

    Influenza viruses are respiratory pathogens that represent a significant threat to public health, despite the large-scale implementation of vaccination programs. It is necessary to understand the detailed and complex interactions between influenza virus and its host cells in order to identify successful strategies for therapeutic intervention. During viral entry, the cellular microenvironment presents invading pathogens with a series of obstacles that must be overcome to infect permissive cells. Influenza hijacks numerous host cell proteins and associated biological pathways during its journey into the cell, responding to environmental cues in order to successfully replicate. The cellular cytoskeleton and its constituent microtubules represent a heavily exploited network during viral infection. Cytoskeletal filaments provide a dynamic scaffold for subcellular viral trafficking, as well as virus-host interactions with cellular machineries that are essential for efficient uncoating, replication, and egress. In addition, influenza virus infection results in structural changes in the microtubule network, which itself has consequences for viral replication. Microtubules, their functional roles in normal cell biology, and their exploitation by influenza viruses will be the focus of this review.

    更新日期:2020-01-17
  • Real Time Analysis of Bovine Viral Diarrhea Virus (BVDV) Infection and Its Dependence on Bovine CD46
    Viruses (IF 3.811) Pub Date : 2020-01-17
    Christiane Riedel; Hann-Wei Chen; Ursula Reichart; Benjamin Lamp; Vibor Laketa; Till Rümenapf

    Virus attachment and entry is a complex interplay of viral and cellular interaction partners. Employing bovine viral diarrhea virus (BVDV) encoding an mCherry-E2 fusion protein (BVDVE2-mCherry), being the first genetically labelled member of the family Flaviviridae applicable for the analysis of virus particles, the early events of infection—attachment, particle surface transport, and endocytosis—were monitored to better understand the mechanisms underlying virus entry and their dependence on the virus receptor, bovine CD46. The analysis of 801 tracks on the surface of SK6 cells inducibly expressing fluorophore labelled bovine CD46 (CD46fluo) demonstrated the presence of directed, diffusive, and confined motion. 26 entry events could be identified, with the majority being associated with a CD46fluo positive structure during endocytosis and occurring more than 20 min after virus addition. Deletion of the CD46fluo E2 binding domain (CD46fluo∆E2bind) did not affect the types of motions observed on the cell surface but resulted in a decreased number of observable entry events (2 out of 1081 tracks). Mean squared displacement analysis revealed a significantly increased velocity of particle transport for directed motions on CD46fluo∆E2bind expressing cells in comparison to CD46fluo. These results indicate that the presence of bovine CD46 is only affecting the speed of directed transport, but otherwise not influencing BVDV cell surface motility. Instead, bovine CD46 seems to be an important factor during uptake, suggesting the presence of additional cellular proteins interacting with the virus which are able to support its transport on the virus surface.

    更新日期:2020-01-17
  • Population- and Variant-Based Genome Analyses of Viruses from Vaccine-Derived Rabies Cases Demonstrate Product Specific Clusters and Unique Patterns
    Viruses (IF 3.811) Pub Date : 2020-01-17
    Sten Calvelage; Marcin Smreczak; Anna Orłowska; Conrad Martin Freuling; Thomas Müller; Christine Fehlner-Gardiner; Susan Nadin-Davis; Dirk Höper; Paweł Trębas

    Rabies in wildlife has been successfully controlled in parts of Europe and North America using oral rabies vaccination, i.e., the distribution of baits containing live-attenuated virus strains. Occasionally, these vaccines caused vaccine virus-induced rabies cases. To elucidate the mechanisms of genetic selection and the effect of viral populations on these rabies cases, a next generation sequencing approach as well as comprehensive data analyses of the genetic diversity of Street Alabama Dufferin (SAD) and ERA vaccine virus strains and vaccine-induced rabies cases from Canada and several European countries were conducted. As a result, twelve newly generated sets of sequencing data from Canada and Poland were added to a pool of previously investigated samples. While the population-based analysis showed a segregation of viruses of ERA vaccine-induced rabies cases from those of SAD Bern original (SAD Bernorig)-derived rabies cases, the in-depth variant analysis revealed three distinct combinations of selected variants for the ERA vaccine-induced cases, suggesting the presence of multiple replication-competent haplotypes in the investigated ERA-BHK21 vaccine. Our findings demonstrate the potential of a deep sequencing approach in combination with comprehensive analyses on the consensus, population, and variant level.

    更新日期:2020-01-17
  • Systematic Identification of Host Immune Key Factors Influencing Viral Infection in PBL of ALV-J Infected SPF Chicken
    Viruses (IF 3.811) Pub Date : 2020-01-16
    Manman Dai; Shibing Li; Keyi Shi; Jiayu Liao; Hui Sun; Ming Liao

    Although research related to avian leukosis virus subgroup J (ALV-J) has lasted for more than a century, the systematic identification of host immune key factors against ALV-J infection has not been reported. In this study, we establish an infection model in which four-week-old SPF chickens are infected with ALV-J strain CHN06, after which the host immune response is detected. We found that the expression of two antiviral interferon-stimulated genes (ISGs) (Mx1 and IFIT5) were increased in ALV-J infected peripheral blood lymphocytes (PBL). A significant CD8+ T cell response induced by ALV-J appeared as early as seven days post-infection (DPI), and humoral immunity starting from 21 DPI differed greatly in the time scale of induction level. Meanwhile, the ALV-J viremia was significantly decreased before antibody production at 14 DPI, and eliminated at 21 DPI under a very low antibody level. The up-regulated CD8+ T cell in the thymus (14DPI) and PBL (7 DPI and 21 DPI) was detected, indicating that the thymus may provide the output of CD8+ T cell to PBL, which was related to virus clearance. Besides, up-regulated chemokine CXCLi1 at 7 DPI in PBL was observed, which may be related to the migration of the CD8+ T cell from the thymus to PBL. More importantly, the CD8 high+ T cell response of the CD8αβ phenotype may produce granzyme K, NK lysin, or IFN-γ for clearing viruses. These findings provide novel insights and direction for developing effective ALV-J vaccines.

    更新日期:2020-01-16
  • Interferon-Gamma Modulation of the Local T Cell Response to Alphavirus Encephalomyelitis
    Viruses (IF 3.811) Pub Date : 2020-01-16
    Victoria K. Baxter; Diane E. Griffin

    Infection of mice with Sindbis virus (SINV) provides a model for examining the role of the immune response to alphavirus infection of the central nervous system (CNS). Interferon-gamma (IFN-γ) is an important component of this response, and we show that SINV-infected differentiated neurons respond to IFN-γ in vitro by induction of antiviral genes and suppression of virus replication. To determine the in vivo effects of IFN-γ on SINV clearance and T cell responses, C57BL/6 mice lacking IFN-γ or IFN-γ receptor-1 were compared to wild-type (WT) mice after intracranial SINV infection. In WT mice, IFN-γ was first produced in the CNS by natural killer cells and then by CD4+ and CD8+ T cells. Mice with impaired IFN-γ signaling initiated clearance of viral RNA earlier than WT mice associated with CNS entry of more granzyme B-producing CD8+ T cells. However, these mice established fewer CD8+ tissue-resident memory T (TRM) cells and were more likely to experience reactivation of viral RNA synthesis late after infection. Therefore, IFN-γ suppresses the local development of granzyme B-expressing CD8+ T cells and slows viral RNA clearance but promotes CD8+ TRM cell establishment.

    更新日期:2020-01-16
  • Herpes Simplex Virus Type-2 Paralyzes the Function of Monocyte-Derived Dendritic Cells
    Viruses (IF 3.811) Pub Date : 2020-01-16
    Linda Grosche; Petra Mühl-Zürbes; Barbara Ciblis; Adalbert Krawczyk; Christine Kuhnt; Lisa Kamm; Alexander Steinkasserer; Christiane Silke Heilingloh

    Herpes simplex viruses not only infect a variety of different cell types, including dendritic cells (DCs), but also modulate important cellular functions in benefit of the virus. Given the relevance of directed immune cell migration during the initiation of potent antiviral immune responses, interference with DC migration constitutes a sophisticated strategy to hamper antiviral immunity. Notably, recent reports revealed that HSV-1 significantly inhibits DC migration in vitro. Thus, we aimed to investigate whether HSV-2 also modulates distinct hallmarks of DC biology. Here, we demonstrate that HSV-2 negatively interferes with chemokine-dependent in vitro migration capacity of mature DCs (mDCs). Interestingly, rather than mediating the reduction of the cognate chemokine receptor expression early during infection, HSV-2 rapidly induces β2 integrin (LFA-1)-mediated mDC adhesion and thereby blocks mDC migration. Mechanistically, HSV-2 triggers the proteasomal degradation of the negative regulator of β2 integrin activity, CYTIP, which causes the constitutive activation of LFA-1 and thus mDC adhesion. In conclusion, our data extend and strengthen recent findings reporting the reduction of mDC migration in the context of a herpesviral infection. We thus hypothesize that hampering antigen delivery to secondary lymphoid organs by inhibition of mDC migration is an evolutionary conserved strategy among distinct members of Herpesviridae.

    更新日期:2020-01-16
  • Host Range Evolution of Potyviruses: A Global Phylogenetic Analysis
    Viruses (IF 3.811) Pub Date : 2020-01-16
    Benoît Moury; Cécile Desbiez

    Virus host range, i.e., the number and diversity of host species of viruses, is an important determinant of disease emergence and of the efficiency of disease control strategies. However, for plant viruses, little is known about the genetic or ecological factors involved in the evolution of host range. Using available genome sequences and host range data, we performed a phylogenetic analysis of host range evolution in the genus Potyvirus, a large group of plant RNA viruses that has undergone a radiative evolution circa 7000 years ago, contemporaneously with agriculture intensification in mid Holocene. Maximum likelihood inference based on a set of 59 potyviruses and 38 plant species showed frequent host range changes during potyvirus evolution, with 4.6 changes per plant species on average, including 3.1 host gains and 1.5 host loss. These changes were quite recent, 74% of them being inferred on the terminal branches of the potyvirus tree. The most striking result was the high frequency of correlated host gains occurring repeatedly in different branches of the potyvirus tree, which raises the question of the dependence of the molecular and/or ecological mechanisms involved in adaptation to different plant species.

    更新日期:2020-01-16
  • Bright and Early: Inhibiting Human Cytomegalovirus by Targeting Major Immediate-Early Gene Expression or Protein Function
    Viruses (IF 3.811) Pub Date : 2020-01-16
    Catherine S. Adamson; Michael M. Nevels

    The human cytomegalovirus (HCMV), one of eight human herpesviruses, establishes lifelong latent infections in most people worldwide. Primary or reactivated HCMV infections cause severe disease in immunosuppressed patients and congenital defects in children. There is no vaccine for HCMV, and the currently approved antivirals come with major limitations. Most approved HCMV antivirals target late molecular processes in the viral replication cycle including DNA replication and packaging. “Bright and early” events in HCMV infection have not been exploited for systemic prevention or treatment of disease. Initiation of HCMV replication depends on transcription from the viral major immediate-early (IE) gene. Alternative transcripts produced from this gene give rise to the IE1 and IE2 families of viral proteins, which localize to the host cell nucleus. The IE1 and IE2 proteins are believed to control all subsequent early and late events in HCMV replication, including reactivation from latency, in part by antagonizing intrinsic and innate immune responses. Here we provide an update on the regulation of major IE gene expression and the functions of IE1 and IE2 proteins. We will relate this insight to experimental approaches that target IE gene expression or protein function via molecular gene silencing and editing or small chemical inhibitors.

    更新日期:2020-01-16
  • Prophylactic Hepatitis E Vaccines: Antigenic Analysis and Serological Evaluation
    Viruses (IF 3.811) Pub Date : 2020-01-16
    Yike Li; Xiaofen Huang; Zhigang Zhang; Shaowei Li; Jun Zhang; Ningshao Xia; Qinjian Zhao

    Hepatitis E virus (HEV) infection causes sporadic outbreaks of acute hepatitis worldwide. HEV was previously considered to be restricted to resource-limited countries with poor sanitary conditions, but increasing evidence implies that HEV is also a public health problem in developed countries and regions. Fortunately, several vaccine candidates based on virus-like particles (VLPs) have progressed into the clinical development stage, and one of them has been approved in China. This review provides an overview of the current HEV vaccine pipeline and future development with the emphasis on defining the critical quality attributes for the well-characterized vaccines. The presence of clinically relevant epitopes on the VLP surface is critical for eliciting functional antibodies against HEV infection, which is the key to the mechanism of action of the prophylactic vaccines against viral infections. Therefore, the epitope-specific immunochemical assays based on monoclonal antibodies (mAbs) for HEV vaccine antigen are critical methods in the toolbox for epitope characterization and for in vitro potency assessment. Moreover, serological evaluation methods after immunization are also discussed as biomarkers for clinical performance. The vaccine efficacy surrogate assays are critical in the preclinical and clinical stages of VLP-based vaccine development.

    更新日期:2020-01-16
  • Virus Metagenomics in Farm Animals: A Systematic Review
    Viruses (IF 3.811) Pub Date : 2020-01-16
    Kirsty T. T. Kwok; David F. Nieuwenhuijse; My V. T. Phan; Marion P. G. Koopmans

    A majority of emerging infectious diseases are of zoonotic origin. Metagenomic Next-Generation Sequencing (mNGS) has been employed to identify uncommon and novel infectious etiologies and characterize virus diversity in human, animal, and environmental samples. Here, we systematically reviewed studies that performed viral mNGS in common livestock (cattle, small ruminants, poultry, and pigs). We identified 2481 records and 120 records were ultimately included after a first and second screening. Pigs were the most frequently studied livestock and the virus diversity found in samples from poultry was the highest. Known animal viruses, zoonotic viruses, and novel viruses were reported in available literature, demonstrating the capacity of mNGS to identify both known and novel viruses. However, the coverage of metagenomic studies was patchy, with few data on the virome of small ruminants and respiratory virome of studied livestock. Essential metadata such as age of livestock and farm types were rarely mentioned in available literature, and only 10.8% of the datasets were publicly available. Developing a deeper understanding of livestock virome is crucial for detection of potential zoonotic and animal pathogens and One Health preparedness. Metagenomic studies can provide this background but only when combined with essential metadata and following the “FAIR” (Findable, Accessible, Interoperable, and Reusable) data principles.

    更新日期:2020-01-16
  • In Vitro Hepatitis C Virus Infection and Hepatic Choline Metabolism
    Viruses (IF 3.811) Pub Date : 2020-01-16
    Kaelan Gobeil Odai; Conor O’Dwyer; Rineke Steenbergen; Tyler A. Shaw; Tyler M. Renner; Peyman Ghorbani; Mojgan Rezaaifar; Shauna Han; Marc-André Langlois; Angela M. Crawley; Rodney S. Russell; John P. Pezacki; D. Lorne Tyrrell; Morgan D. Fullerton

    Choline is an essential nutrient required for normal neuronal and muscular development, as well as homeostatic regulation of hepatic metabolism. In the liver, choline is incorporated into the main eukaryotic phospholipid, phosphatidylcholine (PC), and can enter one-carbon metabolism via mitochondrial oxidation. Hepatitis C virus (HCV) is a hepatotropic positive-strand RNA virus that similar to other positive-strand RNA viruses and can impact phospholipid metabolism. In the current study we sought to interrogate if HCV modulates markers of choline metabolism following in vitro infection, while subsequently assessing if the inhibition of choline uptake and metabolism upon concurrent HCV infection alters viral replication and infectivity. Additionally, we assessed whether these parameters were consistent between cells cultured in fetal bovine serum (FBS) or human serum (HS), conditions known to differentially affect in vitro HCV infection. We observed that choline transport in FBS- and HS-cultured Huh7.5 cells is facilitated by the intermediate affinity transporter, choline transporter-like family (CTL). HCV infection in FBS, but not HS-cultured cells diminished CTL1 transcript and protein expression at 24 h post-infection, which was associated with lower choline uptake and lower incorporation of choline into PC. No changes in other transporters were observed and at 96 h post-infection, all differences were normalized. Reciprocally, limiting the availability of choline for PC synthesis by use of a choline uptake inhibitor resulted in increased HCV replication at this early stage (24 h post-infection) in both FBS- and HS-cultured cells. Finally, in chronic infection (96 h post-infection), inhibiting choline uptake and metabolism significantly impaired the production of infectious virions. These results suggest that in addition to a known role of choline kinase, the transport of choline, potentially via CTL1, might also represent an important and regulated process during HCV infection.

    更新日期:2020-01-16
  • Modeling Challenges of Ebola Virus–Host Dynamics during Infection and Treatment
    Viruses (IF 3.811) Pub Date : 2020-01-16
    Daniel S. Chertow; Louis Shekhtman; Yoav Lurie; Richard T. Davey; Theo Heller; Harel Dahari

    Mathematical modeling of Ebola virus (EBOV)–host dynamics during infection and treatment in vivo is in its infancy due to few studies with frequent viral kinetic data, lack of approved antiviral therapies, and limited insight into the timing of EBOV infection of cells and tissues throughout the body. Current in-host mathematical models simplify EBOV infection by assuming a single homogeneous compartment of infection. In particular, a recent modeling study assumed the liver as the largest solid organ targeted by EBOV infection and predicted that nearly all cells become refractory to infection within seven days of initial infection without antiviral treatment. We compared our observations of EBOV kinetics in multiple anatomic compartments and hepatocellular injury in a critically ill patient with Ebola virus disease (EVD) with this model’s predictions. We also explored the model’s predictions, with and without antiviral therapy, by recapitulating the model using published inputs and assumptions. Our findings highlight the challenges of modeling EBOV–host dynamics and therapeutic efficacy and emphasize the need for iterative interdisciplinary efforts to refine mathematical models that might advance understanding of EVD pathogenesis and treatment.

    更新日期:2020-01-16
  • Reporter Assays for Ebola Virus Nucleoprotein Oligomerization, Virion-Like Particle Budding, and Minigenome Activity Reveal the Importance of Nucleoprotein Amino Acid Position 111
    Viruses (IF 3.811) Pub Date : 2020-01-15
    Aaron E. Lin; William E. Diehl; Yingyun Cai; Courtney L. Finch; Chidiebere Akusobi; Robert N. Kirchdoerfer; Laura Bollinger; Stephen F. Schaffner; Elizabeth A. Brown; Erica Ollmann Saphire; Kristian G. Andersen; Jens H. Kuhn; Jeremy Luban; Pardis C. Sabeti

    For highly pathogenic viruses, reporter assays that can be rapidly performed are critically needed to identify potentially functional mutations for further study under maximal containment (e.g., biosafety level 4 [BSL-4]). The Ebola virus nucleoprotein (NP) plays multiple essential roles during the viral life cycle, yet few tools exist to study the protein under BSL-2 or equivalent containment. Therefore, we adapted reporter assays to measure NP oligomerization and virion-like particle (VLP) production in live cells and further measured transcription and replication using established minigenome assays. As a proof-of-concept, we examined the NP-R111C substitution, which emerged during the 2013‒2016 Western African Ebola virus disease epidemic and rose to high frequency. NP-R111C slightly increased NP oligomerization and VLP budding but slightly decreased transcription and replication. By contrast, a synthetic charge-reversal mutant, NP-R111E, greatly increased oligomerization but abrogated transcription and replication. These results are intriguing in light of recent structures of NP oligomers, which reveal that the neighboring residue, K110, forms a salt bridge with E349 on adjacent NP molecules. By developing and utilizing multiple reporter assays, we find that the NP-111 position mediates a complex interplay between NP’s roles in protein structure, virion budding, and transcription and replication.

    更新日期:2020-01-15
  • An RNA Thermometer Activity of the West Nile Virus Genomic 3′-Terminal Stem-Loop Element Modulates Viral Replication Efficiency during Host Switching
    Viruses (IF 3.811) Pub Date : 2020-01-15
    Alexandra Meyer; Marie Freier; Tobias Schmidt; Katja Rostowski; Juliane Zwoch; Hauke Lilie; Sven-Erik Behrens; Susann Friedrich

    The 3′-terminal stem-loop (3′SL) of the RNA genome of the flavivirus West Nile (WNV) harbors, in its stem, one of the sequence elements that are required for genome cyclization. As cyclization is a prerequisite for the initiation of viral replication, the 3′SL was proposed to act as a replication silencer. The lower part of the 3′SL is metastable and confers a structural flexibility that may regulate the switch from the linear to the circular conformation of the viral RNA. In the human system, we previously demonstrated that a cellular RNA-binding protein, AUF1 p45, destabilizes the 3′SL, exposes the cyclization sequence, and thus promotes flaviviral genome cyclization and RNA replication. By investigating mutant RNAs with increased 3′SL stabilities, we showed the specific conformation of the metastable element to be a critical determinant of the helix-destabilizing RNA chaperone activity of AUF1 p45 and of the precision and efficiency of the AUF1 p45-supported initiation of RNA replication. Studies of stability-increasing mutant WNV replicons in human and mosquito cells revealed that the cultivation temperature considerably affected the replication efficiencies of the viral RNA variants and demonstrated the silencing effect of the 3′SL to be temperature dependent. Furthermore, we identified and characterized mosquito proteins displaying similar activities as AUF1 p45. However, as the RNA remodeling activities of the mosquito proteins were found to be considerably lower than those of the human protein, a potential cell protein-mediated destabilization of the 3′SL was suggested to be less efficient in mosquito cells. In summary, our data support a model in which the 3′SL acts as an RNA thermometer that modulates flavivirus replication during host switching.

    更新日期:2020-01-15
  • Contribution of Dendritic Cells in Protective Immunity against Respiratory Syncytial Virus Infection
    Viruses (IF 3.811) Pub Date : 2020-01-15
    Hi Eun Jung; Tae Hoon Kim; Heung Kyu Lee

    Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and the elderly. The socioeconomic burden of RSV infection is substantial because it leads to serious respiratory problems, subsequent hospitalization, and mortality. Despite its clinical significance, a safe and effective vaccine is not yet available to prevent RSV infection. Upon RSV infection, lung dendritic cells (DCs) detecting pathogens migrate to the lymph nodes and activate the adaptive immune response. Therefore, RSV has evolved various immunomodulatory strategies to inhibit DC function. Due to the capacity of RSV to modulate defense mechanisms in hosts, RSV infection results in inappropriate activation of immune responses resulting in immunopathology and frequent reinfection throughout life. This review discusses how DCs recognize invading RSV and induce adaptive immune responses, as well as the regulatory mechanisms mediated by RSV to disrupt DC functions and ultimately avoid host defenses.

    更新日期:2020-01-15
  • Real-Time Analysis of Individual Ebola Virus Glycoproteins Reveals Pre-Fusion, Entry-Relevant Conformational Dynamics
    Viruses (IF 3.811) Pub Date : 2020-01-15
    Natasha D. Durham; Angela R. Howard; Ramesh Govindan; Fernando Senjobe; J. Maximilian Fels; William E. Diehl; Jeremy Luban; Kartik Chandran; James B. Munro

    The Ebola virus (EBOV) envelope glycoprotein (GP) mediates the fusion of the virion membrane with the membrane of susceptible target cells during infection. While proteolytic cleavage of GP by endosomal cathepsins and binding of the cellular receptor Niemann-Pick C1 protein (NPC1) are essential steps for virus entry, the detailed mechanisms by which these events promote membrane fusion remain unknown. Here, we applied single-molecule Förster resonance energy transfer (smFRET) imaging to investigate the structural dynamics of the EBOV GP trimeric ectodomain, and the functional transmembrane protein on the surface of pseudovirions. We show that in both contexts, pre-fusion GP is dynamic and samples multiple conformations. Removal of the glycan cap and NPC1 binding shift the conformational equilibrium, suggesting stabilization of conformations relevant to viral fusion. Furthermore, several neutralizing antibodies enrich alternative conformational states. This suggests that these antibodies neutralize EBOV by restricting access to GP conformations relevant to fusion. This work demonstrates previously unobserved dynamics of pre-fusion EBOV GP and presents a platform with heightened sensitivity to conformational changes for the study of GP function and antibody-mediated neutralization.

    更新日期:2020-01-15
  • Hepatitis C Virus Affects Tuberculosis-Specific T Cells in HIV-Negative Patients
    Viruses (IF 3.811) Pub Date : 2020-01-15
    Mohamed Ahmed El-Mokhtar; Sherein G. Elgendy; Abeer Sharaf Eldin; Elham Ahmed Hassan; Ali Abdel Azeem Hasan; Muhamad R. Abdel Hameed; Douaa Sayed; Eman H. Salama

    The occurrence of tuberculosis (TB) and hepatitis C virus (HCV) infections in the same patient presents a unique clinical challenge. The impact of HCV infection on the immune response to TB remains poorly investigated in TB+/HCV+ patients. This study was conducted to evaluate the impact of HCV on the T-cell-mediated immune response to TB in coinfected patients. Sixty-four patients with active TB infections were screened for coinfection with HCV. The expression of immune activation markers IFN-γ, CD38, and HLA-DR on TB-specific CD4+ T cells was evaluated by flow cytometry in TB-monoinfected patients, TB/HCV-coinfected patients, and healthy controls. IL-2, IL-4, IFN-γ, TNF-α, and IL-10 levels were measured using ELISA. The end-of-treatment response to anti-TB therapy was recorded for both patient groups. Significantly lower levels of CD4+IFN-γ+CD38+ and CD4+IFN-γ+HLA-DR+ T cells were detected in TB/HCV-coinfected patients compared to TB monoinfected patients and controls. TB+/HCV+-coinfected patients showed higher serum levels of IL-10. The baseline frequencies of TB-specific activated T-cell subsets did not predict the response to antituberculous therapy in TB+/HCV+ patients. We concluded that different subsets of TB-specific CD4+ T cells in TB/HCV-infected individuals are partially impaired in early-stage HCV infection. This was combined with increased serum IL-10 level. Such immune modulations may represent a powerful risk factor for disease progression in patients with HCV/TB coinfection.

    更新日期:2020-01-15
  • Development of a Multiplex RT-qPCR for the Detection of Different Clades of Avian Influenza in Poultry
    Viruses (IF 3.811) Pub Date : 2020-01-15
    Tran Bac Le; Hye Kwon Kim; Woonsung Na; Van Phan Le; Min-Suk Song; Daesub Song; Dae Gwin Jeong; Sun-Woo Yoon

    Since the initial detection of H5N1, a highly pathogenic avian influenza (HPAI) virus, in 1996 in China, numerous HPAI H5 lineages have been classified, and they continue to pose a threat to animal and human health. In this study, we developed a novel primer/probe set that can be employed to simultaneously detect pan-H5 HPAI and two clades, 2.3.2.1 and 2.3.4.4, of H5Nx viruses using reverse transcription quantitative polymerase chain reaction (RT-qPCR). The sensitivity and specificity of these primer sets and probes were confirmed with a number of different subtypes of influenza virus and the H5-HA gene plasmid DNA. In particular, the multiplex RT-qPCR assay was successfully applied to the simultaneous detection of H5 HPAI and different virus clades in clinical field samples from a poultry farm. Therefore, this multiplex assay and a novel detection primer set and probes will be useful for the laboratory diagnosis and epidemiological field studies of different circulating H5 HPAI virus clades in poultry and migratory wild birds.

    更新日期:2020-01-15
  • Detection and Molecular Characterization of Picobirnaviruses (PBVs) in the Mongoose: Identification of a Novel PBV Using an Alternative Genetic Code
    Viruses (IF 3.811) Pub Date : 2020-01-15
    Alyssa Kleymann; Anne A. M. J. Becker; Yashpal S. Malik; Nobumichi Kobayashi; Souvik Ghosh

    We report high rates of detection (35.36%, 29/82) of genogroup-I (GI) picobirnaviruses (PBVs) in non-diarrheic fecal samples from the small Indian mongoose (Urva auropunctata). In addition, we identified a novel PBV-like RNA-dependent RNA polymerase (RdRp) gene sequence that uses an alternative mitochondrial genetic code (that of mold or invertebrate) for translation. The complete/nearly complete gene segment-2/RdRp gene sequences of seven mongoose PBV GI strains and the novel PBV-like strain were obtained by combining a modified non-specific primer-based amplification method with conventional RT-PCRs, facilitated by the inclusion of a new primer targeting the 3′-untranslated region (UTR) of PBV gene segment-2. The mongoose PBV and PBV-like strains retained the various features that are conserved in gene segment-2/RdRps of other PBVs. However, high genetic diversity was observed among the mongoose PBVs within and between host species. This is the first report on detection of PBVs in the mongoose. Molecular characterization of the PBV and PBV-like strains from a new animal species provided important insights into the various features and complex diversity of PBV gene segment-2/putative RdRps. The presence of the prokaryotic ribosomal binding site in the mongoose PBV genomes, and analysis of the novel PBV-like RdRp gene sequence that uses an alternative mitochondrial genetic code (especially that of mold) for translation corroborated recent speculations that PBVs may actually infect prokaryotic or fungal host cells.

    更新日期:2020-01-15
  • Distinct MCM10 Proteasomal Degradation Profiles by Primate Lentiviruses Vpr Proteins
    Viruses (IF 3.811) Pub Date : 2020-01-15
    Hao Chang; Lowela Siarot; Ryosuke Matsuura; Chieh-Wen Lo; Hirotaka Sato; Hiroyuki Otsuki; Yoko Aida

    Viral protein R (Vpr) is an accessory protein found in various primate lentiviruses, including human immunodeficiency viruses type 1 and 2 (HIV-1 and HIV-2) as well as simian immunodeficiency viruses (SIVs). Vpr modulates many processes during viral lifecycle via interaction with several of cellular targets. Previous studies showed that HIV-1 Vpr strengthened degradation of Mini-chromosome Maintenance Protein10 (MCM10) by manipulating DCAF1-Cul4-E3 ligase in proteasome-dependent pathway. However, whether Vpr from other primate lentiviruses are also associated with MCM10 degradation and the ensuing impact remain unknown. Based on phylogenetic analyses, a panel of primate lentiviruses Vpr/x covering main virus lineages was prepared. Distinct MCM10 degradation profiles were mapped and HIV-1, SIVmus and SIVrcm Vprs induced MCM10 degradation in proteasome-dependent pathway. Colocalization and interaction between MCM10 with these Vprs were also observed. Moreover, MCM10 2-7 interaction region was identified as a determinant region susceptible to degradation. However, MCM10 degradation did not alleviate DNA damage response induced by these Vpr proteins. MCM10 degradation by HIV-1 Vpr proteins was correlated with G2/M arrest, while induction of apoptosis and oligomerization formation of Vpr failed to alter MCM10 proteolysis. The current study demonstrated a distinct interplay pattern between primate lentiviruses Vpr proteins and MCM10.

    更新日期:2020-01-15
  • Chronic Hepatitis B Virus Infection Associated with Increased Colorectal Cancer Risk in Taiwanese Population
    Viruses (IF 3.811) Pub Date : 2020-01-14
    Fu-Hsiung Su; Thi Nga Le; Chih-Hsin Muo; Sister Arlene Te; Fung-Chang Sung; Chih-Ching Yeh

    Chronic hepatitis B virus (HBV) infections and colorectal cancer (CRC) are prevalent in Taiwan. We carried out a population-based case-control study to assess the association between HBV infection and CRC risk. Using the National Health Insurance Research Database of Taiwan, we identified 69,478 newly diagnosed patients with CRC from 2005 to 2011. We further randomly selected 69,478 age- and gender-matched controls without CRC from the same database. Odds ratios (ORs) were calculated to evaluate the association between chronic HBV infection and CRC using a logistic regression analysis. HBV infection was found to be associated with the risk of CRC (OR = 1.27, 95% confidence interval (CI) = 1.20–1.33). This relationship was similar in men and women. Age-specific analysis revealed that the CRC risk associated with HBV decreased with age. The adjusted ORs for patients aged <55, 55–64, and 65–74 years were 1.63 (95% CI = 1.48–1.79), 1.24 (95% CI = 1.13–1.37), and 1.02 (95% = 0.92–1.13), respectively. In conclusion, this study suggests that chronic HBV infection is significantly associated with an increased risk of CRC. Monitoring the risk of CRC development in young patients with HBV infection is crucial.

    更新日期:2020-01-15
  • Usefulness of Clinical Definitions of Influenza for Public Health Surveillance Purposes
    Viruses (IF 3.811) Pub Date : 2020-01-14
    Àngela Domínguez; Núria Soldevila; Núria Torner; Ana Martínez; Pere Godoy; Cristina Rius; Mireia Jané; the PIDIRAC Sentinel Surveillance Program of Catalonia

    This study investigated the performance of various case definitions and influenza symptoms in a primary healthcare sentinel surveillance system. A retrospective study of the clinical and epidemiological characteristics of the cases reported by a primary healthcare sentinel surveillance network for eleven years in Catalonia was conducted. Crude and adjusted diagnostic odds ratios (aDORs) and 95% confidence intervals (CIs) of the case definitions and symptoms for all weeks and epidemic weeks were estimated. The most predictive case definition for laboratory-confirmed influenza was the World Health Organization (WHO) case definition for ILI in all weeks (aDOR 2.69; 95% CI 2.42–2.99) and epidemic weeks (aDOR 2.20; 95% CI 1.90–2.54). The symptoms that were significant positive predictors for confirmed influenza were fever, cough, myalgia, headache, malaise, and sudden onset. Fever had the highest aDOR in all weeks (4.03; 95% CI 3.38–4.80) and epidemic weeks (2.78; 95% CI 2.21–3.50). All of the case definitions assessed performed better in patients with comorbidities than in those without. The performance of symptoms varied by age groups, with fever being of high value in older people, and cough being of high value in children. In patients with comorbidities, the performance of fever was the highest (aDOR 5.45; 95% CI 3.43–8.66). No differences in the performance of the case definition or symptoms in influenza cases according to virus type were found.

    更新日期:2020-01-15
  • Origin of Bluetongue Virus Serotype 8 Outbreak in Cyprus, September 2016
    Viruses (IF 3.811) Pub Date : 2020-01-14
    Paulina Rajko-Nenow; Vasiliki Christodoulou; William Thurston; Honorata M. Ropiak; Savvas Savva; Hannah Brown; Mehnaz Qureshi; Konstantinos Alvanitopoulos; Simon Gubbins; John Flannery; Carrie Batten

    In September 2016, clinical signs, indicative of bluetongue, were observed in sheep in Cyprus. Bluetongue virus serotype 8 (BTV-8) was detected in sheep, indicating the first incursion of this serotype into Cyprus. Following virus propagation, Nextera XT DNA libraries were sequenced on the MiSeq instrument. Full-genome sequences were obtained for five isolates CYP2016/01-05 and the percent of nucleotide sequence (% nt) identity between them ranged from 99.92% to 99.95%, which corresponded to a few (2–5) amino acid changes. Based on the complete coding sequence, the Israeli ISR2008/13 (98.42–98.45%) was recognised as the closest relative to CYP2016/01-05. However, the phylogenetic reconstruction of CYP2016/01-05 revealed that the possibility of reassortment in several segments: 4, 7, 9 and 10. Based on the available sequencing data, the incursion BTV-8 into Cyprus most likely occurred from the neighbouring countries (e.g., Israel, Lebanon, Syria, or Jordan), where multiple BTV serotypes were co-circulating rather than from Europe (e.g., France) where a single BTV-8 serotype was dominant. Supporting this hypothesis, atmospheric dispersion modelling identified wind-transport events during July–September that could have allowed the introduction of BTV-8 infected midges from Lebanon, Syria or Israel coastlines into the Larnaca region of Cyprus.

    更新日期:2020-01-15
  • Discovery and Prevalence of Divergent RNA Viruses in European Field Voles and Rabbits
    Viruses (IF 3.811) Pub Date : 2020-01-14
    Theocharis Tsoleridis; Joseph G. Chappell; Elodie Monchatre-Leroy; Gérald Umhang; Mang Shi; Malcolm Bennett; Rachael E. Tarlinton; C Patrick McClure; Edward C. Holmes; Jonathan K. Ball

    The advent of unbiased metagenomic virus discovery has revolutionized studies of virus biodiversity and evolution. Despite this, our knowledge of the virosphere, including in mammalian species, remains limited. We used unbiased metagenomic sequencing to identify RNA viruses in European field voles and rabbits. Accordingly, we identified a number of novel RNA viruses including astrovirus, rotavirus A, picorna-like virus and a morbilli-like paramyxovirus. In addition, we identified a sobemovirus and a novel luteovirus that likely originated from the rabbit diet. These newly discovered viruses were often divergent from those previously described. The novel astrovirus was most closely related to a virus sampled from the rodent-eating European roller bird (Coracias garrulous). PCR screening revealed that the novel morbilli-like paramyxovirus in the UK field vole had a prevalence of approximately 4%, and shared common ancestry with other rodent morbilli-like viruses sampled globally. Two novel rotavirus A sequences were detected in a UK field vole and a French rabbit, the latter with a prevalence of 5%. Finally, a highly divergent picorna-like virus found in the gut of the French rabbit virus was only ~35% similar to an arilivirus at the amino acid level, suggesting the presence of a novel viral genus within the Picornaviridae.

    更新日期:2020-01-14
  • Special Issue “Human Picornaviruses”
    Viruses (IF 3.811) Pub Date : 2020-01-13
    Petri Susi

    Note: In lieu of an abstract, this is an excerpt from the first page. The Special Issue “Human Picornaviruses” in “Viruses” (Submission Deadline 30 September 2019, https://www.mdpi.com/journal/viruses/special_issues/Picornaviruses) includes twelve original articles and four reviews with a wide range of topics [...]

    更新日期:2020-01-13
  • Characterization of Ebola Virus Disease (EVD) in Rhesus Monkeys for Development of EVD Therapeutics
    Viruses (IF 3.811) Pub Date : 2020-01-13
    Travis Warren; Elizabeth Zumbrun; Jessica M. Weidner; Laura Gomba; Franco Rossi; Roy Bannister; Jacqueline Tarrant; Matthew Reed; Eric Lee; Jo Lynne Raymond; Jay Wells; Joshua Shamblin; Kelly Wetzel; Ginger Donnelly; Sean Van Tongeren; Nicole Lackemeyer; Jesse Steffens; Adrienne Kimmel; Carly Garvey; Holly Bloomfield; Christiana Blair; Bali Singh; Sina Bavari; Tomas Cihlar; Danielle Porter

    Recent Ebola virus (EBOV) outbreaks in West Africa and the Democratic Republic of the Congo have highlighted the urgent need for approval of medical countermeasures for treatment and prevention of EBOV disease (EVD). Until recently, when successes were achieved in characterizing the efficacy of multiple experimental EVD therapeutics in humans, the only feasible way to obtain data regarding potential clinical benefits of candidate therapeutics was by conducting well-controlled animal studies. Nonclinical studies are likely to continue to be important tools for screening and development of new candidates with improved pharmacological properties. Here, we describe a natural history study to characterize the time course and order of progression of the disease manifestations of EVD in rhesus monkeys. In 12 rhesus monkeys exposed by the intramuscular route to 1000 plaque-forming units of EBOV, multiple endpoints were monitored for 28 days following exposure. The disease progressed rapidly with mortality events occurring 7–10 days after exposure. Key disease manifestations observed consistently across the infected animals included, but were not limited to, viremia, fever, systemic inflammation, coagulopathy, lymphocytolysis, renal tubular necrosis with mineralization, and hepatocellular degeneration and necrosis.

    更新日期:2020-01-13
  • Single Amino Acid Substitutions in the Cucumber Mosaic Virus 1a Protein Induce Necrotic Cell Death in Virus-Inoculated Leaves without Affecting Virus Multiplication
    Viruses (IF 3.811) Pub Date : 2020-01-13
    Ainan Tian; Shuhei Miyashita; Sugihiro Ando; Hideki Takahashi

    When Arabidopsis thaliana ecotype Col-0 was inoculated with a series of reassortant viruses created by exchanging viral genomic RNAs between two strains of cucumber mosaic virus (CMV), CMV(Y), and CMV(H), cell death developed in the leaves inoculated with reassortant CMV carrying CMV(H) RNA1 encoding 1a protein, but not in noninoculated upper leaves. In general, cell death in virus-infected plants is a critical event for virus survival because virus multiplication is completely dependent on host cell metabolism. However, interestingly, this observed cell death did not affect either virus multiplication in the inoculated leaves or systemic spread to noninoculated upper leaves. Furthermore, the global gene expression pattern of the reassortant CMV-inoculated leaves undergoing cell death was clearly different from that in hypersensitive response (HR) cell death, which is coupled with resistance to CMV. These results indicated that the observed cell death does not appear to be HR cell death but rather necrotic cell death unrelated to CMV resistance. Interestingly, induction of this necrotic cell death depended on single amino acid substitutions in the N-terminal region surrounding the methyltransferase domain of the 1a protein. Thus, development of necrotic cell death might not be induced by non-specific damage as a result of virus multiplication, but by a virus protein-associated mechanism. The finding of CMV 1a protein-mediated induction of necrotic cell death in A. thaliana, which is not associated with virus resistance and HR cell death, has the potential to provide a new pathosystem to study the role of cell death in virus–host plant interactions.

    更新日期:2020-01-13
  • Glycine Cleavage System and cAMP Receptor Protein Co-Regulate CRISPR/cas3 Expression to Resist Bacteriophage
    Viruses (IF 3.811) Pub Date : 2020-01-13
    Denghui Yang; Zhaofei Wang; Jingjiao Ma; Qiang Fu; Lifei Wu; Hengan Wang; Shaohui Wang; Yaxian Yan; Jianhe Sun

    The CRISPR/Cas system protects bacteria against bacteriophage and plasmids through a sophisticated mechanism where cas operon plays a crucial role consisting of cse1 and cas3. However, comprehensive studies on the regulation of cas3 operon of the Type I-E CRISPR/Cas system are scarce. Herein, we investigated the regulation of cas3 in Escherichia coli. The mutation in gcvP or crp reduced the CRISPR/Cas system interference ability and increased bacterial susceptibility to phage, when the casA operon of the CRISPR/Cas system was activated. The silence of the glycine cleavage system (GCS) encoded by gcvTHP operon reduced cas3 expression. Adding N5, N10-methylene tetrahydrofolate (N5, N10-mTHF), which is the product of GCS-catalyzed glycine, was able to activate cas3 expression. In addition, a cAMP receptor protein (CRP) encoded by crp activated cas3 expression via binding to the cas3 promoter in response to cAMP concentration. Since N5, N10-mTHF provides one-carbon unit for purine, we assumed GCS regulates cas3 through associating with CRP. It was evident that the mutation of gcvP failed to further reduce the cas3 expression with the crp deletion. These results illustrated a novel regulatory pathway which GCS and CRP co-regulate cas3 of the CRISPR/Cas system and contribute to the defence against invasive genetic elements, where CRP is indispensable for GCS regulation of cas3 expression.

    更新日期:2020-01-13
  • Epidemiology and Clinical Characteristics of Influenza C Virus
    Viruses (IF 3.811) Pub Date : 2020-01-13
    Bethany K. Sederdahl; John V. Williams

    Influenza C virus (ICV) is a common yet under-recognized cause of acute respiratory illness. ICV seropositivity has been found to be as high as 90% by 7–10 years of age, suggesting that most people are exposed to ICV at least once during childhood. Due to difficulty detecting ICV by cell culture, epidemiologic studies of ICV likely have underestimated the burden of ICV infection and disease. Recent development of highly sensitive RT-PCR has facilitated epidemiologic studies that provide further insights into the prevalence, seasonality, and course of ICV infection. In this review, we summarize the epidemiology and clinical characteristics of ICV.

    更新日期:2020-01-13
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