Publications by authors named "Peter Simmonds"

267 Publications

Potential APOBEC-mediated RNA editing of the genomes of SARS-CoV-2 and other coronaviruses and its impact on their longer term evolution.

Virology 2021 04 7;556:62-72. Epub 2021 Jan 7.

Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, OX13SY, UK. Electronic address:

Members of the APOBEC family of cytidine deaminases show antiviral activities in mammalian cells through lethal editing in the genomes of small DNA viruses, herpesviruses and retroviruses, and potentially those of RNA viruses such as coronaviruses. Consistent with the latter, APOBEC-like directional C→U transitions of genomic plus-strand RNA are greatly overrepresented in SARS-CoV-2 genome sequences of variants emerging during the COVID-19 pandemic. A C→U mutational process may leave evolutionary imprints on coronavirus genomes, including extensive homoplasy from editing and reversion at targeted sites and the occurrence of driven amino acid sequence changes in viral proteins. If sustained over longer periods, this process may account for the previously reported marked global depletion of C and excess of U bases in human seasonal coronavirus genomes. This review synthesizes the current knowledge on APOBEC evolution and function and the evidence of their role in APOBEC-mediated genome editing of SARS-CoV-2 and other coronaviruses.
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http://dx.doi.org/10.1016/j.virol.2020.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831814PMC
April 2021

Unexpected nascent atmospheric emissions of three ozone-depleting hydrochlorofluorocarbons.

Proc Natl Acad Sci U S A 2021 Feb;118(5)

Climate Science Centre, CSIRO Oceans and Atmosphere, Commonwealth Scientific and Industrial Research Organisation, Aspendale, VIC 3195, Australia.

Global and regional atmospheric measurements and modeling can play key roles in discovering and quantifying unexpected nascent emissions of environmentally important substances. We focus here on three hydrochlorofluorocarbons (HCFCs) that are restricted by the Montreal Protocol because of their roles in stratospheric ozone depletion. Based on measurements of archived air samples and on in situ measurements at stations of the Advanced Global Atmospheric Gases Experiment (AGAGE) network, we report global abundances, trends, and regional enhancements for HCFC-132b ([Formula: see text]), which is newly discovered in the atmosphere, and updated results for HCFC-133a ([Formula: see text]) and HCFC-31 ([Formula: see text]ClF). No purposeful end-use is known for any of these compounds. We find that HCFC-132b appeared in the atmosphere 20 y ago and that its global emissions increased to 1.1 Gg⋅y by 2019. Regional top-down emission estimates for East Asia, based on high-frequency measurements for 2016-2019, account for ∼95% of the global HCFC-132b emissions and for ∼80% of the global HCFC-133a emissions of 2.3 Gg⋅y during this period. Global emissions of HCFC-31 for the same period are 0.71 Gg⋅y Small European emissions of HCFC-132b and HCFC-133a, found in southeastern France, ceased in early 2017 when a fluorocarbon production facility in that area closed. Although unreported emissive end-uses cannot be ruled out, all three compounds are most likely emitted as intermediate by-products in chemical production pathways. Identification of harmful emissions to the atmosphere at an early stage can guide the effective development of global and regional environmental policy.
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http://dx.doi.org/10.1073/pnas.2010914118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865182PMC
February 2021

Association of Zinc Finger Antiviral Protein Binding to Viral Genomic RNA with Attenuation of Replication of Echovirus 7.

mSphere 2021 01 6;6(1). Epub 2021 Jan 6.

Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom

Previous studies have implicated both zinc finger antiviral protein (ZAP) and oligoadenylate synthetase 3 (OAS3)/RNase L in the attenuation of RNA viruses with elevated CpG and UpA dinucleotides. Mechanisms and interrelationships between these two pathways were investigated using an echovirus 7 (E7) replicon with compositionally modified sequences inserted into the 3' untranslated region. ZAP and OAS3 immunoprecipitation (IP) assays provided complementary data on dinucleotide composition effects on binding. Elevated frequencies of alternative pyrimidine/purine (CpA and UpG) and reversed (GpC and ApU) dinucleotides showed no attenuating effect on replication or specific binding to ZAP by IP. However, the bases 3' and 5' of CpG motifs influenced replication and ZAP binding; UCGU enhanced CpG-mediated attenuation and ZAP binding, while A residues shielded CpGs from ZAP recognition. Attenuating effects of elevated frequencies of UpA on replication occurred independently of CpG dinucleotides and bound noncompetitively with CpG-enriched RNA, consistent with a separate recognition site from CpG. Remarkably, immunoprecipitation with OAS3 antibody reproduced the specific binding to CpG- and UpA-enriched RNA sequences. However, OAS3 and ZAP were coimmunoprecipitated in both ZAP and OAS3 IP and colocalized with E7 and stress granules (SGs) by confocal microscopy analysis of infected cells. ZAP's association with larger cellular complexes may mediate the recruitment of OAS3/RNase L, KHNYN, and other RNA degradation pathways. We recently discovered that the OAS3/RNase L antiviral pathway is essential for restriction of CpG- and UpA-enriched viruses, in addition to the requirement for zinc finger antiviral protein (ZAP). The current study provides evidence for the specific dinucleotide and wider recognition contexts associated with virus recognition and attenuation. It further documents the association of ZAP and OAS3 and association with stress granules and a wider protein interactome that may mediate antiviral effects in different cellular compartments. The study provides a striking reconceptualization of the pathways associated with this aspect of antiviral defense.
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http://dx.doi.org/10.1128/mSphere.01138-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845596PMC
January 2021

Convalescent plasma therapy for the treatment of patients with COVID-19: Assessment of methods available for antibody detection and their correlation with neutralising antibody levels.

Transfus Med 2020 Dec 17. Epub 2020 Dec 17.

NHS Blood and Transplant, Oxford, John Radcliffe Hospital, Oxford, UK.

Introduction: The lack of approved specific therapeutic agents to treat coronavirus disease (COVID-19) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to the rapid implementation of convalescent plasma therapy (CPT) trials in many countries, including the United Kingdom. Effective CPT is likely to require high titres of neutralising antibody (nAb) in convalescent donations. Understanding the relationship between functional neutralising antibodies and antibody levels to specific SARS-CoV-2 proteins in scalable assays will be crucial for the success of a large-scale collection. We assessed whether neutralising antibody titres correlated with reactivity in a range of enzyme-linked immunosorbent assays (ELISA) targeting the spike (S) protein, the main target for human immune response.

Methods: Blood samples were collected from 52 individuals with a previous laboratory-confirmed SARS-CoV-2 infection. These were assayed for SARS-CoV-2 nAbs by microneutralisation and pseudo-type assays and for antibodies by four different ELISAs. Receiver operating characteristic (ROC) analysis was used to further identify sensitivity and specificity of selected assays to identify samples containing high nAb levels.

Results: All samples contained SARS-CoV-2 antibodies, whereas neutralising antibody titres of greater than 1:20 were detected in 43 samples (83% of those tested) and >1:100 in 22 samples (42%). The best correlations were observed with EUROimmun immunoglobulin G (IgG) reactivity (Spearman Rho correlation coefficient 0.88; p < 0.001). Based on ROC analysis, EUROimmun would detect 60% of samples with titres of >1:100 with 100% specificity using a reactivity index of 9.1 (13/22).

Discussion: Robust associations between nAb titres and reactivity in several ELISA-based antibody tests demonstrate their possible utility for scaled-up production of convalescent plasma containing potentially therapeutic levels of anti-SARS-CoV-2 nAbs.
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http://dx.doi.org/10.1111/tme.12746DOI Listing
December 2020

Understanding the outcomes of COVID-19 - does the current model of an acute respiratory infection really fit?

J Gen Virol 2020 Dec 17. Epub 2020 Dec 17.

National Microbiology Services, NHS Blood and Transplant, London, UK.

Although coronavirus disease 2019 (COVID-19) is regarded as an acute, resolving infection followed by the development of protective immunity, recent systematic literature review documents evidence for often highly prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory and faecal samples, periodic recurrence of PCR positivity in a substantial proportion of individuals and increasingly documented instances of reinfection associated with a lack of protective immunity. This pattern of infection is quite distinct from the acute/resolving nature of other human pathogenic respiratory viruses, such as influenza A virus and respiratory syncytial virus. Prolonged shedding of SARS-CoV-2 furthermore occurs irrespective of disease severity or development of virus-neutralizing antibodies. SARS-CoV-2 possesses an intensely structured RNA genome, an attribute shared with other human and veterinary coronaviruses and with other mammalian RNA viruses such as hepatitis C virus. These are capable of long-term persistence, possibly through poorly understood RNA structure-mediated effects on innate and adaptive host immune responses. The assumption that resolution of COVID-19 and the appearance of anti-SARS-CoV-2 IgG antibodies represents virus clearance and protection from reinfection, implicit for example in the susceptible-infected-recovered (SIR) model used for epidemic prediction, should be rigorously re-evaluated.
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http://dx.doi.org/10.1099/jgv.0.001545DOI Listing
December 2020

SARS-CoV-2 RNA detected in blood products from patients with COVID-19 is not associated with infectious virus.

Wellcome Open Res 2020 12;5:181. Epub 2020 Oct 12.

Public Health England, 61 Colindale Ave, London, NW9 5EQ, UK.

Laboratory diagnosis of SARS-CoV-2 infection (the cause of COVID-19) uses PCR to detect viral RNA (vRNA) in respiratory samples. SARS-CoV-2 RNA has also been detected in other sample types, but there is limited understanding of the clinical or laboratory significance of its detection in blood. We undertook a systematic literature review to assimilate the evidence for the frequency of vRNA in blood, and to identify associated clinical characteristics. We performed RT-PCR in serum samples from a UK clinical cohort of acute and convalescent COVID-19 cases (n=212), together with convalescent plasma samples collected by NHS Blood and Transplant (NHSBT) (n=462 additional samples). To determine whether PCR-positive blood samples could pose an infection risk, we attempted virus isolation from a subset of RNA-positive samples. We identified 28 relevant studies, reporting SARS-CoV-2 RNA in 0-76% of blood samples; pooled estimate 10% (95%CI 5-18%). Among serum samples from our clinical cohort, 27/212 (12.7%) had SARS-CoV-2 RNA detected by RT-PCR. RNA detection occurred in samples up to day 20 post symptom onset, and was associated with more severe disease (multivariable odds ratio 7.5). Across all samples collected ≥28 days post symptom onset, 0/494 (0%, 95%CI 0-0.7%) had vRNA detected. Among our PCR-positive samples, cycle threshold (ct) values were high (range 33.5-44.8), suggesting low vRNA copy numbers. PCR-positive sera inoculated into cell culture did not produce any cytopathic effect or yield an increase in detectable SARS-CoV-2 RNA. There was a relationship between RT-PCR negativity and the presence of total SARS-CoV-2 antibody (p=0.02). vRNA was detectable at low viral loads in a minority of serum samples collected in acute infection, but was not associated with infectious SARS-CoV-2 (within the limitations of the assays used). This work helps to inform biosafety precautions for handling blood products from patients with current or previous COVID-19.
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http://dx.doi.org/10.12688/wellcomeopenres.16002.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689603PMC
October 2020

Recommendations for the introduction of metagenomic high-throughput sequencing in clinical virology, part I: Wet lab procedure.

J Clin Virol 2021 Jan 18;134:104691. Epub 2020 Nov 18.

Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Metagenomic high-throughput sequencing (mHTS) is a hypothesis-free, universal pathogen detection technique for determination of the DNA/RNA sequences in a variety of sample types and infectious syndromes. mHTS is still in its early stages of translating into clinical application. To support the development, implementation and standardization of mHTS procedures for virus diagnostics, the European Society for Clinical Virology (ESCV) Network on Next-Generation Sequencing (ENNGS) has been established. The aim of ENNGS is to bring together professionals involved in mHTS for viral diagnostics to share methodologies and experiences, and to develop application recommendations. This manuscript aims to provide practical recommendations for the wet lab procedures necessary for implementation of mHTS for virus diagnostics and to give recommendations for development and validation of laboratory methods, including mHTS quality assurance, control and quality assessment protocols.
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http://dx.doi.org/10.1016/j.jcv.2020.104691DOI Listing
January 2021

Detection of neutralising antibodies to SARS-CoV-2 to determine population exposure in Scottish blood donors between March and May 2020.

Euro Surveill 2020 10;25(42)

Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.

BackgroundThe progression and geographical distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United Kingdom (UK) and elsewhere is unknown because typically only symptomatic individuals are diagnosed. We performed a serological study of blood donors in Scotland in the spring of 2020 to detect neutralising antibodies to SARS-CoV-2 as a marker of past infection and epidemic progression.AimOur objective was to determine if sera from blood bank donors can be used to track the emergence and progression of the SARS-CoV-2 epidemic.MethodsA pseudotyped SARS-CoV-2 virus microneutralisation assay was used to detect neutralising antibodies to SARS-CoV-2. The study comprised samples from 3,500 blood donors collected in Scotland between 17 March and 18 May 2020. Controls were collected from 100 donors in Scotland during 2019.ResultsAll samples collected on 17 March 2020 (n = 500) were negative in the pseudotyped SARS-CoV-2 virus microneutralisation assay. Neutralising antibodies were detected in six of 500 donors from 23 to 26 March. The number of samples containing neutralising antibodies did not significantly rise after 5-6 April until the end of the study on 18 May. We found that infections were concentrated in certain postcodes, indicating that outbreaks of infection were extremely localised. In contrast, other areas remained comparatively untouched by the epidemic.ConclusionAlthough blood donors are not representative of the overall population, we demonstrated that serosurveys of blood banks can serve as a useful tool for tracking the emergence and progression of an epidemic such as the SARS-CoV-2 outbreak.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.42.2000685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651873PMC
October 2020

2020 taxonomic update for phylum Negarnaviricota (Riboviria: Orthornavirae), including the large orders Bunyavirales and Mononegavirales.

Authors:
Jens H Kuhn Scott Adkins Daniela Alioto Sergey V Alkhovsky Gaya K Amarasinghe Simon J Anthony Tatjana Avšič-Županc María A Ayllón Justin Bahl Anne Balkema-Buschmann Matthew J Ballinger Tomáš Bartonička Christopher Basler Sina Bavari Martin Beer Dennis A Bente Éric Bergeron Brian H Bird Carol Blair Kim R Blasdell Steven B Bradfute Rachel Breyta Thomas Briese Paul A Brown Ursula J Buchholz Michael J Buchmeier Alexander Bukreyev Felicity Burt Nihal Buzkan Charles H Calisher Mengji Cao Inmaculada Casas John Chamberlain Kartik Chandran Rémi N Charrel Biao Chen Michela Chiumenti Il-Ryong Choi J Christopher S Clegg Ian Crozier John V da Graça Elena Dal Bó Alberto M R Dávila Juan Carlos de la Torre Xavier de Lamballerie Rik L de Swart Patrick L Di Bello Nicholas Di Paola Francesco Di Serio Ralf G Dietzgen Michele Digiaro Valerian V Dolja Olga Dolnik Michael A Drebot Jan Felix Drexler Ralf Dürrwald Lucie Dufkova William G Dundon W Paul Duprex John M Dye Andrew J Easton Hideki Ebihara Toufic Elbeaino Koray Ergünay Jorlan Fernandes Anthony R Fooks Pierre B H Formenty Leonie F Forth Ron A M Fouchier Juliana Freitas-Astúa Selma Gago-Zachert George Fú Gāo María Laura García Adolfo García-Sastre Aura R Garrison Aiah Gbakima Tracey Goldstein Jean-Paul J Gonzalez Anthony Griffiths Martin H Groschup Stephan Günther Alexandro Guterres Roy A Hall John Hammond Mohamed Hassan Jussi Hepojoki Satu Hepojoki Udo Hetzel Roger Hewson Bernd Hoffmann Seiji Hongo Dirk Höper Masayuki Horie Holly R Hughes Timothy H Hyndman Amara Jambai Rodrigo Jardim Dàohóng Jiāng Qi Jin Gilda B Jonson Sandra Junglen Serpil Karadağ Karen E Keller Boris Klempa Jonas Klingström Gary Kobinger Hideki Kondō Eugene V Koonin Mart Krupovic Gael Kurath Ivan V Kuzmin Lies Laenen Robert A Lamb Amy J Lambert Stanley L Langevin Benhur Lee Elba R S Lemos Eric M Leroy Dexin Li Jiànróng Lǐ Mifang Liang Wénwén Liú Yàn Liú Igor S Lukashevich Piet Maes William Marciel de Souza Marco Marklewitz Sergio H Marshall Giovanni P Martelli Robert R Martin Shin-Yi L Marzano Sébastien Massart John W McCauley Nicole Mielke-Ehret Angelantonio Minafra Maria Minutolo Ali Mirazimi Hans-Peter Mühlbach Elke Mühlberger Rayapati Naidu Tomohide Natsuaki Beatriz Navarro José A Navarro Sergey V Netesov Gabriele Neumann Norbert Nowotny Márcio R T Nunes Are Nylund Arnfinn L Økland Renata C Oliveira Gustavo Palacios Vicente Pallas Bernadett Pályi Anna Papa Colin R Parrish Alex Pauvolid-Corrêa Janusz T Pawęska Susan Payne Daniel R Pérez Florian Pfaff Sheli R Radoshitzky Aziz-Ul Rahman Pedro L Ramos-González Renato O Resende Carina A Reyes Bertus K Rima Víctor Romanowski Gabriel Robles Luna Paul Rota Dennis Rubbenstroth Jonathan A Runstadler Daniel Ruzek Sead Sabanadzovic Jiří Salát Amadou Alpha Sall Maria S Salvato Kamil Sarpkaya Takahide Sasaya Martin Schwemmle Muhammad Z Shabbir Xiǎohóng Shí Zhènglì Shí Yukio Shirako Peter Simmonds Jana Širmarová Manuela Sironi Sophie Smither Teemu Smura Jin-Won Song Kirsten M Spann Jessica R Spengler Mark D Stenglein David M Stone Petra Straková Ayato Takada Robert B Tesh Natalie J Thornburg Keizō Tomonaga Noël Tordo Jonathan S Towner Massimo Turina Ioannis Tzanetakis Rainer G Ulrich Anna Maria Vaira Bernadette van den Hoogen Arvind Varsani Nikos Vasilakis Martin Verbeek Victoria Wahl Peter J Walker Hui Wang Jianwei Wang Xifeng Wang Lin-Fa Wang Tàiyún Wèi Heather Wells Anna E Whitfield John V Williams Yuri I Wolf Zhìqiáng Wú Xin Yang Xīnglóu Yáng Xuejie Yu Natalya Yutin F Murilo Zerbini Tong Zhang Yong-Zhen Zhang Guohui Zhou Xueping Zhou

Arch Virol 2020 Dec 4;165(12):3023-3072. Epub 2020 Sep 4.

State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing, China.

In March 2020, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. At the genus rank, 20 new genera were added, two were deleted, one was moved, and three were renamed. At the species rank, 160 species were added, four were deleted, ten were moved and renamed, and 30 species were renamed. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.
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http://dx.doi.org/10.1007/s00705-020-04731-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606449PMC
December 2020

Broad and strong memory CD4 and CD8 T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19.

Nat Immunol 2020 11 4;21(11):1336-1345. Epub 2020 Sep 4.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4 and/or CD8 epitopes, including six immunodominant regions. Six optimized CD8 epitopes were defined, with peptide-MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8 T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.
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http://dx.doi.org/10.1038/s41590-020-0782-6DOI Listing
November 2020

Human cytomegalovirus evades ZAP detection by suppressing CpG dinucleotides in the major immediate early 1 gene.

PLoS Pathog 2020 09 4;16(9):e1008844. Epub 2020 Sep 4.

Division of Infection and Immunity, The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, United Kingdom.

The genomes of RNA and small DNA viruses of vertebrates display significant suppression of CpG dinucleotide frequencies. Artificially increasing dinucleotide frequencies results in substantial attenuation of virus replication, suggesting that these compositional changes may facilitate recognition of non-self RNA sequences. Recently, the interferon inducible protein ZAP, was identified as the host factor responsible for sensing CpG in viral RNA, through direct binding and possibly downstream targeting for degradation. Using an arrayed interferon stimulated gene expression library screen, we identified ZAPS, and its associated factor TRIM25, as inhibitors of human cytomegalovirus (HCMV) replication. Exogenous expression of ZAPS and TRIM25 significantly reduced virus replication while knockdown resulted in increased virus replication. HCMV displays a strikingly heterogeneous pattern of CpG representation with specific suppression of CpG motifs within the IE1 major immediate early transcript which is absent in subsequently expressed genes. We demonstrated that suppression of CpG dinucleotides in the IE1 gene allows evasion of inhibitory effects of ZAP. We show that acute virus replication is mutually exclusive with high levels of cellular ZAP, potentially explaining the higher levels of CpG in viral genes expressed subsequent to IE1 due to the loss of pressure from ZAP in infected cells. Finally, we show that TRIM25 regulates alternative splicing between the ZAP short and long isoforms during HCMV infection and interferon induction, with knockdown of TRIM25 resulting in decreased ZAPS and corresponding increased ZAPL expression. These results demonstrate for the first time that ZAP is a potent host restriction factor against large DNA viruses and that HCMV evades ZAP detection through suppression of CpG dinucleotides within the major immediate early 1 transcript. Furthermore, TRIM25 is required for efficient upregulation of the interferon inducible short isoform of ZAP through regulation of alternative splicing.
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http://dx.doi.org/10.1371/journal.ppat.1008844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498042PMC
September 2020

Molecular epidemiology and clinical impact of rhinovirus infections in adults during three epidemic seasons in 11 European countries (2007-2010).

Thorax 2020 10 20;75(10):882-890. Epub 2020 Aug 20.

Medical Microbiology, Leiden Universitair Medisch Centrum, Leiden, The Netherlands

Background: Differences in clinical impact between rhinovirus (RVs) species and types in adults are not well established. The objective of this study was to determine the epidemiology and clinical impact of the different RV species.

Methods: We conducted a prospective study of RVs infections in adults with acute cough/lower respiratory tract infection (LRTI) and asymptomatic controls. Subjects were recruited from 16 primary care networks located in 11 European countries between 2007 and 2010. RV detection and genotyping was performed by means of real time and conventional reverse-transcriptase polymerase chain reaction assays, followed by sequence analysis. Clinical data were obtained from medical records and patient symptom diaries.

Results: RVs were detected in 566 (19%) of 3016 symptomatic adults, 102 (4%) of their 2539 follow-up samples and 67 (4%) of 1677 asymptomatic controls. Genotyping was successful for 538 (95%) symptomatic subjects, 86 (84%) follow-up infections and 62 (93%) controls. RV-A was the prevailing species, associated with an increased risk of LRTI as compared with RV-B (relative risk (RR), 4.5; 95% CI 2.5 to 7.9; p<0.001) and RV-C (RR 2.2; 95% CI 1.2 to 3.9; p=0.010). In symptomatic subjects, RV-A loads were higher than those of RV-B (p=0.015). Symptom scores and duration were similar across species. More RV-A infected patients felt generally unwell in comparison to RV-C (p=0·023). Of the 140 RV types identified, five were new types; asymptomatic infections were associated with multiple types.

Interpretation: In adults, RV-A is significantly more often detected in cases with acute cough/LRTI than RV-C, while RV-B infection is often found in asymptomatic patients.
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http://dx.doi.org/10.1136/thoraxjnl-2019-214317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509388PMC
October 2020

Changes to virus taxonomy and the Statutes ratified by the International Committee on Taxonomy of Viruses (2020).

Arch Virol 2020 Nov;165(11):2737-2748

Departamento de Fitopatologia/BIOAGRO, Universidade Federal de Viçosa, Viçosa, MG, 36570-900, Brazil.

This article reports the changes to virus classification and taxonomy approved and ratified by the International Committee on Taxonomy of Viruses (ICTV) in March 2020. The entire ICTV was invited to vote on 206 taxonomic proposals approved by the ICTV Executive Committee at its meeting in July 2019, as well as on the proposed revision of the ICTV Statutes. All proposals and the revision of the Statutes were approved by an absolute majority of the ICTV voting membership. Of note, ICTV has approved a proposal that extends the previously established realm Riboviria to encompass nearly all RNA viruses and reverse-transcribing viruses, and approved three separate proposals to establish three realms for viruses with DNA genomes.
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http://dx.doi.org/10.1007/s00705-020-04752-xDOI Listing
November 2020

Use of a small DNA virus model to investigate mechanisms of CpG dinucleotide-induced attenuation of virus replication.

J Gen Virol 2020 Nov;101(11):1202-1218

Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, UK.

Suppression of the CpG dinucleotide is widespread in RNA viruses infecting vertebrates and plants, and in the genomes of retroviruses and small mammalian DNA viruses. The functional basis for CpG suppression in the latter was investigated through the construction of mutants of the parvovirus, minute virus of mice (MVM) with increased CpG or TpA dinucleotides in the VP gene. CpG-high mutants displayed extraordinary attenuation in A9 cells compared to wild-type MVM (>six logs), while TpA elevation showed no replication effect. Attenuation was independent of Toll-like receptor 9 and STING-mediated DNA recognition pathways and unrelated to effects on translation efficiency. While translation from codon-optimized VP RNA was enhanced in a cell-free assay, MVM containing this sequence was highly attenuated. Further mutational analysis indicated that this arose through its increased numbers of CpG dinucleotides (7→70) and separately from its increased G+C content (42.3→57.4 %), which independently attenuated replication. CpG-high viruses showed impaired NS mRNA expression by qPCR and reduced NS and particularly VP protein expression detected by immunofluorescence and replication in A549 cells, effects reversed in zinc antiviral protein (ZAP) knockout cells, even though nuclear relocalization of VP remained defective. The demonstrated functional basis for CpG suppression in MVM and potentially other small DNA viruses and the observed intolerance of CpGs in coding sequences, even after codon optimization, has implications for the use of small DNA virus vectors in gene therapy and immunization.
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http://dx.doi.org/10.1099/jgv.0.001477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879557PMC
November 2020

The First Nonmammalian Pegivirus Demonstrates Efficient Replication and High Lymphotropism.

J Virol 2020 09 29;94(20). Epub 2020 Sep 29.

Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu City, Sichuan Province, China

Members of the genus, family widely infect humans and other mammals, including nonhuman primates, bats, horses, pigs, and rodents, but are not associated with disease. Here, we report a new, genetically distinct pegivirus in goose (), the first identified in a nonmammalian host species. Goose pegivirus (GPgV) can be propagated in goslings, embryonated goose eggs, and primary goose embryo fibroblasts, and is thus the first pegivirus that can be efficiently cultured Experimental infection of GPgV in goslings via intravenous injection revealed robust replication and high lymphotropism. Analysis of the tissue tropism of GPgV revealed that the spleen and thymus were the organs bearing the highest viral loads. Importantly, GPgV could promote clinical manifestations of goose parvovirus infection, including reduced weight gain and 7% mortality. This finding contrasts with the lack of pathogenicity that is characteristic of previously reported pegiviruses. Members of the genus, family , widely infect humans and other mammals, but are described as causing persistent infection and lacking pathogenicity. The efficiency of replication systems for pegivirus is poor, thus limiting investigation into viral replication steps. Because of that, the pathogenesis, cellular tropism, route of transmission, biology, and epidemiology of pegiviruses remain largely uncovered. Here, we report a phylogenetically distinct goose pegivirus (GPgV) that should be classified as a new species. GPgV proliferated in cell culture in a species- and cell-type-specific manner. Animal experiments show GPgV lymphotropism and promote goose parvovirus clinical manifestations. This study provides the first cell culture model for pegivirus, opening new possibilities for studies of pegivirus molecular biology. More importantly, our findings stand in contrast to the lack of identified pathogenicity of previously reported pegiviruses, which sheds lights on the pathobiology of pegivirus.
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http://dx.doi.org/10.1128/JVI.01150-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527067PMC
September 2020

Impact of virus subtype and host genotype on large-scale RNA structure formation in the genome of hepatitis C virus.

RNA 2020 11 3;26(11):1541-1556. Epub 2020 Aug 3.

Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, OX1 3SY, Oxford, United Kingdom.

Mechanisms underlying the ability of hepatitis C virus (HCV) to establish persistent infections and induce progressive liver disease remain poorly understood. HCV is one of several positive-stranded RNA viruses capable of establishing persistence in their immunocompetent vertebrate hosts, an attribute previously associated with formation of large-scale RNA structure in their genomic RNA. We developed novel methods to analyze and visualize genome-scale ordered RNA structure (GORS) predicted from the increasingly large data sets of complete genome sequences of HCV. Structurally conserved RNA secondary structure in coding regions of HCV localized exclusively to polyprotein ends (core, NS5B). Coding regions elsewhere were also intensely structured based on elevated minimum folding energy difference (MFED) values, but the actual stem-loop elements involved in genome folding were structurally poorly conserved, even between subtypes 1a and 1b. Dynamic remodeling was further evident from comparison of HCV strains in different host genetic backgrounds. Significantly higher MFED values, greater suppression of UpA dinucleotide frequencies, and restricted diversification were found in subjects with the TT genotype of the rs12979860 SNP in the gene compared to the CC (nonexpressing) allele. These structural and compositional associations with expression of interferon-λ4 were recapitulated on a larger scale by higher MFED values and greater UpA suppression of genotype 1 compared to genotype 3a, associated with previously reported HCV genotype-associated differences in hepatic interferon-stimulated gene induction. Associations between innate cellular responses with HCV structure and further evolutionary constraints represent an important new element in RNA virus evolution and the adaptive interplay between virus and host.
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http://dx.doi.org/10.1261/rna.075465.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566573PMC
November 2020

Convalescent plasma treatment for SARS-CoV-2 infection: analysis of the first 436 donors in England, 22 April to 12 May 2020.

Euro Surveill 2020 Jul;25(28)

The members of the NHS Blood and Transplant Convalescent Plasma Testing Group are listed below.

Serological reactivity was analysed in plasma from 436 individuals with a history of disease compatible with COVID-19, including 256 who had been laboratory-confirmed with SARS-CoV-2 infection. Over 99% of laboratory-confirmed cases developed a measurable antibody response (254/256) and 88% harboured neutralising antibodies (226/256). Antibody levels declined over 3 months following diagnosis, emphasising the importance of the timing of convalescent plasma collections. Binding antibody measurements can inform selection of convalescent plasma donors with high neutralising antibody levels.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.28.2001260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376844PMC
July 2020

Recombination Analysis of Non-Poliovirus Members of the Enterovirus C Species; Restriction of Recombination Events to Members of the Same 3DPol Cluster.

Viruses 2020 06 30;12(7). Epub 2020 Jun 30.

Department of Medical Microbiology, Location Academic Medical Center (AMC), Amsterdam University Medical Centers (Amsterdam UMC), 1105AZ Amsterdam, The Netherlands.

Enteroviruses (EVs) are highly prevalent viruses worldwide. Recombination is known to occur frequently in EVs belonging to species , , and . Although many recombinant vaccine-derived poliovirus (VDPV) strains have been reported, our knowledge on recombination in non-polio EVs in the species is limited. Here, we combined a dataset consisting of 11 newly generated full-length sequences and 180 publicly available sequences to study recombination dynamics in non-polio EVs. To identify recombination patterns, maximum likelihood phylogenetic trees of different genomic regions were constructed, and segregation analyses were performed. Recombination was observed between members of the same 3DPol cluster, but was rarely observed between members of different clusters. We hypothesize that this restriction may have arisen through their different compartmentalization in respiratory and enteric tracts related to differences in cellular tropisms so that the opportunity to recombine may not be available.
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http://dx.doi.org/10.3390/v12070706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412211PMC
June 2020

Broad and strong memory CD4 and CD8 T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients.

bioRxiv 2020 Jun 8. Epub 2020 Jun 8.

COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFNγ based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4 and/or CD8 epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8 T cells than spike-specific CD8 T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8 to CD4 T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design.
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http://dx.doi.org/10.1101/2020.06.05.134551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302222PMC
June 2020

Efficacy of NS5A inhibitors against unusual and potentially difficult-to-treat HCV subtypes commonly found in sub-Saharan Africa and South East Asia.

J Hepatol 2020 Oct 26;73(4):794-799. Epub 2020 May 26.

Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.

Background & Aims: The efficacy of NS5A inhibitors against several less common subtypes of hepatitis C virus (HCV) is poorly characterised. Some subtypes including 3b, 3g, 6u and 6v commonly harbour amino acid residues in NS5A that may confer resistance to direct-acting antivirals (DAAs) in other common subtypes. Data from patients also suggest that 1l and 4r with amino acid substitutions at positions 28-31 and 93 in NS5A are relatively resistant to DAA therapy.

Methods: In this study, we tested the efficacy of daclatasvir, elbasvir, ledipasvir, pibrentasvir and velpatasvir against these subtypes using the SGR-JFH1 replicon backbone.

Results: NS5A inhibitors showed different levels of efficacy with only pibrentasvir effective against all tested subtypes. Daclatasvir and ledipasvir were ineffective against 6u and 6v (half maximal effective concentration [EC] values of 239-321 nM) while 3b and 3g were only susceptible to pibrentasvir. Analysis of effects of individual mutations indicated that Q30R in 1l increased the EC of ledipasvir by 18-fold, conferring intermediate resistance, while those of L31M and Y93H in 4r induced increases in EC values of 2,100- and 3,575-fold (high-level resistance).

Conclusion: The high ledipasvir EC values of 1l with the Q30R substitution, 4r L31M and 4r Y93H may explain the treatment failure in patients who were infected with these viruses and treated with ledipasvir + sofosbuvir. This study also shows the ineffectiveness of the first generation NS5A inhibitors against 6u and 6v, and confirms the inherent resistance of 3b and 3g to most NS5A inhibitors. Clinical studies to confirm in vivo sensitivity to NS5A inhibitors are urgently needed so that rational, effective treatment strategies may be developed for unusual subtypes.

Lay Summary: Little is known about the efficacy of NS5A inhibitors against some "unusual" hepatitis C virus (HCV) subtypes including 1l, 3b, 3g, 4r, 6u and 6v. In this study, we manufactured HCV replicons which express the NS5A protein from the unusual HCV subtypes 1l, 3b, 3g, 4r, 6u, 6v. We then tested the effect of the NS5A inhibitors daclatasvir, elbasvir, ledipasvir, pibrentasvir and velpatasvir on blocking replication, using these replicons. We show that these replicons are resistant at some level to all NS5A inhibitors other than pibrentasvir.
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http://dx.doi.org/10.1016/j.jhep.2020.05.029DOI Listing
October 2020

Update: proposed reference sequences for subtypes of hepatitis E virus (species ).

J Gen Virol 2020 07;101(7):692-698

Centers for Disease Control and Prevention, National Center for HIV/Hepatitis/STD/TB Prevention, Division of Viral Hepatitis, Atlanta, Georgia, USA.

In this recommendation, we update our 2016 table of reference sequences of subtypes of hepatitis E virus (HEV; species , family ) for which complete genome sequences are available (Smith ., 2016). This takes into account subsequent publications describing novel viruses and additional proposals for subtype names; there are now eight genotypes and 36 subtypes. Although it remains difficult to define strict criteria for distinguishing between virus subtypes, and is not within the remit of the International Committee on Taxonomy of Viruses (ICTV), the use of agreed reference sequences will bring clarity and stability to researchers, epidemiologists and clinicians working with HEV.
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http://dx.doi.org/10.1099/jgv.0.001435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660235PMC
July 2020

Perforin and resistance to SARS coronavirus 2.

J Allergy Clin Immunol 2020 Jul 15;146(1):52-53. Epub 2020 May 15.

St John's Institute of Dermatology, Guy's and St Thomas' Hospital, London, United Kingdom.

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http://dx.doi.org/10.1016/j.jaci.2020.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255292PMC
July 2020

Real-world experience with doxorubicin and olaratumab in soft tissue sarcomas in England and Northern Ireland.

Clin Sarcoma Res 2020 6;10. Epub 2020 May 6.

1Sarcoma Unit, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ UK.

Background: A randomised phase II trial demonstrated that the addition of olaratumab to doxorubicin significantly increased overall survival (OS) in patients with advanced soft tissue sarcomas (STS) compared to doxorubicin alone. The recently presented phase III study of doxorubicin and olaratumab in advanced soft tissue sarcoma was discordant with this finding.

Methods: We performed a retrospective analysis of adult patients with advanced-/metastatic STS treated with at least two cycles of doxorubicin and olaratumab at eight sarcoma units across England and Northern Ireland between May 2017 and March 2019.

Results: 172 patients were evaluable and 40 patients (23.3%) had died at the time of analysis. Median ECOG performance status (PS) was 1. Median progression free survival (PFS) was 6.8 months (95% CI 5.9-7.7 months). Leiomyosarcoma was the most common histological subtype (75 patients, 43.6%), followed by liposarcomas (19, 11.0%). The mean number of cycles was 5 (doxorubicin range 2-6; olaratumab range 2-23). Two patients (1.2%) had a complete response and 34 (19.8%) had a partial response. 79 (45.9%) had stable and 58 (33.7%) progressive disease. 57 patients (33.1%) experienced grade ≥ 3 neutropenia and 7 patients (4.1%) grade ≥ 3 febrile neutropenia. Grade ≥ 3 anaemia was seen in 21 patients (12.2%). Grade ≥ 3 non-haematological toxicities were seen in 35 patients (20.3%). A clinically significant drop in left ventricular ejection fraction was seen in 6 patients (3.5%). 48 patients (27.9%) required a dose reduction. Overall survival (OS) is pending.

Conclusions: Our results are in keeping with the phase III study findings: response rate, PFS and OS were similar to those reported in the phase III ANNOUNCE trial.
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http://dx.doi.org/10.1186/s13569-020-00131-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203838PMC
May 2020

Survival and disease characteristics of de novo versus recurrent metastatic breast cancer in a cohort of young patients.

Br J Cancer 2020 May 31;122(11):1618-1629. Epub 2020 Mar 31.

University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, SO16 6YD, UK.

Background: It is not clear how the pathology, presentation and outcome for patients who present with de novo metastatic breast cancer (dnMBC) compare with those who later develop distant metastases. DnMBC is uncommon in younger patients. We describe these differences within a cohort of young patients in the United Kingdom.

Methods: Women aged 40 years or younger with a first invasive breast cancer were recruited to the prospective POSH national cohort study. Baseline clinicopathological data were collected, with annual follow-up. Overall survival (OS) and post-distant relapse-free survival (PDRS) were assessed using Kaplan-Meier curves.

Results: In total, 862 patients were diagnosed with metastatic disease. DnMBC prevalence was 2.6% (76/2977). Of those with initially localised disease, 27.1% (786/2901) subsequently developed a distant recurrence. Median follow-up was 11.00 years (95% CI 10.79-11.59). Patients who developed metastatic disease within 12 months had worse OS than dnMBC patients (HR 2.64; 1.84-3.77). For PDRS, dnMBC was better than all groups, including those who relapsed after 5 years. Of dnMBC patients, 1.3% had a gBRCA1, and 11.8% a gBRCA2 mutation.

Conclusions: Young women with dnMBC have better PDRS than those who develop relapsed metastatic breast cancer. A gBRCA2 mutation was overrepresented in dnMBC.
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http://dx.doi.org/10.1038/s41416-020-0784-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250836PMC
May 2020

Plant Virus Genome Is Shaped by Specific Dinucleotide Restrictions That Influence Viral Infection.

mBio 2020 02 18;11(1). Epub 2020 Feb 18.

Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain

The presence of CpG and UpA dinucleotides is restricted in the genomes of animal RNA viruses to avoid specific host defenses. We wondered whether a similar phenomenon exists in nonanimal RNA viruses. Here, we show that these two dinucleotides, especially UpA, are underrepresented in the family , the most important group of plant RNA viruses. Using plum pox virus (PPV; family) as a model, we show that an increase in UpA frequency strongly diminishes virus accumulation. Remarkably, unlike previous observations in animal viruses, PPV variants harboring CpG-rich fragments display just faint (or no) attenuation. The anticorrelation between UpA frequency and viral fitness additionally demonstrates the relevance of this particular dinucleotide: UpA-high mutants are attenuated in a dose-dependent manner, whereas a UpA-low variant displays better fitness than its parental control. Using high-throughput sequencing, we also show that UpA-rich PPV variants are genetically stable, without apparent changes in sequence that revert and/or compensate for the dinucleotide modification despite its attenuation. In addition, we also demonstrate here that the PPV restriction of UpA-rich variants works independently of the classical RNA silencing pathway. Finally, we show that the anticorrelation between UpA frequency and RNA accumulation applies to mRNA-like fragments produced by the host RNA polymerase II. Together, our results inform us about a dinucleotide-based system in plant cells that controls diverse RNAs, including RNA viruses. Dinucleotides (combinations of two consecutive nucleotides) are not randomly present in RNA viruses; in fact, the presence of CpG and UpA is significantly repressed in their genomes. Although the meaning of this phenomenon remains obscure, recent studies with animal-infecting viruses have revealed that their low CpG/UpA frequency prevents virus restriction via a host antiviral system that recognizes, and promotes the degradation of, CpG/UpA-rich RNAs. Whether similar systems act in organisms from other life kingdoms has been unknown. To fill this gap in our knowledge, we built several synthetic variants of a plant RNA virus with deoptimized dinucleotide frequencies and analyzed their viral fitness and genome adaptation. In brief, our results inform us for the first time about an effective dinucleotide-based system that acts in plants against viruses. Remarkably, this viral restriction in plants is reminiscent of, but not identical to, the equivalent antiviral response in animals.
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http://dx.doi.org/10.1128/mBio.02818-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029135PMC
February 2020

Correction to: Binomial nomenclature for virus species: a consultation.

Arch Virol 2020 05;165(5):1263-1264

MRC-University of Glasgow Centre for Virus Research, Sir Michael Stoker Building, 464 Bearsden Road, Glasgow, G61 1QH, UK.

The article Binomial nomenclature for virus species: a consultation, written by Stuart G. Siddell, Peter J. Walker, Elliot J. Lefkowitz, Arcady R. Mushegian, Bas E. Dutilh.
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http://dx.doi.org/10.1007/s00705-020-04555-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160066PMC
May 2020

How to recognise and deal with dubious virus sequences?

Infect Genet Evol 2020 07 13;81:104242. Epub 2020 Feb 13.

Max F. Perutz Laboratories, Medical University Vienna, Vienna, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.meegid.2020.104242DOI Listing
July 2020

Potential for diagnosis of infectious disease from the 100,000 Genomes Project Metagenomic Dataset: Recommendations for reporting results.

Wellcome Open Res 2019 14;4:155. Epub 2019 Oct 14.

University of East Anglia, Norwich, UK.

The identification of microbiological infection is usually a diagnostic investigation, a complex process that is firstly initiated by clinical suspicion. With the emergence of high-throughput sequencing (HTS) technologies, metagenomic analysis has unveiled the power to identify microbial DNA/RNA from a diverse range of clinical samples (1). Metagenomic analysis of whole human genomes at the clinical/research interface bypasses the steps of clinical scrutiny and targeted testing and has the potential to generate unexpected findings relating to infectious and sometimes transmissible disease. There is no doubt that microbial findings that may have a significant impact on a patient's treatment and their close contacts should be reported to those with clinical responsibility for the sample-donating patient. There are no clear recommendations on how such findings that are incidental, or outside the original investigation, should be handled. Here we aim to provide an informed protocol for the management of incidental microbial findings as part of the 100,000 Genomes Project which may have broader application in this emerging field. As with any other clinical information, we aim to prioritise the reporting of data that are most likely to be of benefit to the patient and their close contacts. We also set out to minimize risks, costs and potential anxiety associated with the reporting of results that are unlikely to be of clinical significance. Our recommendations aim to support the practice of microbial metagenomics by providing a simplified pathway that can be applied to reporting the identification of potential pathogens from metagenomic datasets. Given that the ambition for UK sequenced human genomes over the next 5 years has been set to reach 5 million and the field of metagenomics is rapidly evolving, the guidance will be regularly reviewed and will likely adapt over time as experience develops.
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http://dx.doi.org/10.12688/wellcomeopenres.15499.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993825PMC
October 2019

Circulation of non-polio enteroviruses in 24 EU and EEA countries between 2015 and 2017: a retrospective surveillance study.

Lancet Infect Dis 2020 03 20;20(3):350-361. Epub 2019 Dec 20.

Microbiology Services, National Health Service (NHS) Blood and Transplant, London, UK; Division of Infection and Immunity, University College London, London, UK. Electronic address:

Background: Enteroviruses can cause severe infections, especially in young children. Non-polio enterovirus infections are not notifiable in most countries in the EU and European Economic Area (EEA) region, and surveillance varies substantially between countries. We collected and analysed available enterovirus data across EU and EEA countries to assess the current epidemiological situation and need for standardising surveillance.

Methods: Aggregated data on any enterovirus detected between Jan 1, 2015, and Dec 31, 2017, through national enterovirus reference laboratories were requested from representatives in all 31 EU and EEA countries. Information collected included enterovirus types detected by month, patient age group, symptom, and specimen type. We also collected sequence data on viral capsid sequences for the three most clinically relevant enterovirus types, as identified from the data.

Findings: Aggregated data were provided by representatives from 24 (77%) of 31 countries. 9914 (66%) of 14 999 enterovirus infections with information about age were in children younger than 5 years, and 3197 (45%) of 7139 individuals for whom symptoms were reported had neurological symptoms. Other symptoms were non-specific fever (in 1607 [23%] patients), respiratory symptoms (in 1197 [17%] patients), hand, foot, and mouth disease (in 528 [7% patients), and myocarditis (in 39 [1%] patients). 68 deaths were temporally associated with enterovirus infection. Typing for 11 559 (67%) of 17 136 specimens revealed 66 enterovirus types. Coxsackievirus A6 was the most frequently detected enterovirus type (in 1556 [13%] of 11 559 typed enteroviruses), and 292 (65%) of 448 patients with coxsackievirus A6 infection with available clinical data presented with hand, foot, and mouth disease. Echovirus 30 was the second most frequently detected enterovirus type, representing 1412 (12%) of 11 559 typed enteroviruses, and 384 (82%) of 467 individuals with echovirus 30 infection with available clinical data had neurological symptoms. Sequences available from 18 countries showed circulation of newly emerging strains of enterovirus A71 and enterovirus D68.

Interpretation: To our knowledge, this study is the largest investigation of enterovirus circulation in EU and EEA countries and confirms the availability of non-polio enterovirus data in the region. Our study highlights the wide circulation of non-polio enteroviruses in Europe, mostly affecting young children and leading to neurological symptoms. Collecting data on morbidity and mortality related to enterovirus infections, as well as harmonising case definition for surveillance, should be encouraged.

Funding: None.
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http://dx.doi.org/10.1016/S1473-3099(19)30566-3DOI Listing
March 2020

A functional investigation of the suppression of CpG and UpA dinucleotide frequencies in plant RNA virus genomes.

Sci Rep 2019 12 4;9(1):18359. Epub 2019 Dec 4.

Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, OX1 3SY, UK.

Frequencies of CpG and UpA dinucleotides in most plant RNA virus genomes show degrees of suppression comparable to those of vertebrate RNA viruses. While pathways that target CpG and UpAs in HIV-1 and echovirus 7 genomes and restrict their replication have been partly characterised, whether an analogous process drives dinucleotide underrepresentation in plant viruses remains undetermined. We examined replication phenotypes of compositionally modified mutants of potato virus Y (PVY) in which CpG or UpA frequencies were maximised in non-structural genes (including helicase and polymerase encoding domains) while retaining protein coding. PYV mutants with increased CpG dinucleotide frequencies showed a dose-dependent reduction in systemic spread and pathogenicity and up to 1000-fold attenuated replication kinetics in distal sites on agroinfiltration of tobacco plants (Nicotiana benthamiana). Even more extraordinarily, comparably modified UpA-high mutants displayed no pathology and over a million-fold reduction in replication. Tobacco plants with knockdown of RDP6 displayed similar attenuation of CpG- and UpA-high mutants suggesting that restriction occurred independently of the plant siRNA antiviral responses. Despite the evolutionary gulf between plant and vertebrate genomes and encoded antiviral strategies, these findings point towards the existence of novel virus restriction pathways in plants functionally analogous to innate defence components in vertebrate cells.
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http://dx.doi.org/10.1038/s41598-019-54853-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892864PMC
December 2019