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  1. Article ; Online: The roles of nucleic acid editing in adaptation of zoonotic viruses to humans.

    Ratcliff, Jeremy / Simmonds, Peter

    Current opinion in virology

    2023  Volume 60, Page(s) 101326

    Abstract: Following spillover, viruses must adapt to new selection pressures exerted by antiviral responses in their new hosts. In mammals, cellular defense mechanisms often include viral nucleic acid editing pathways mediated through protein families ... ...

    Abstract Following spillover, viruses must adapt to new selection pressures exerted by antiviral responses in their new hosts. In mammals, cellular defense mechanisms often include viral nucleic acid editing pathways mediated through protein families apolipoprotein-B mRNA-editing complex (APOBEC) and Adenosine Deaminase Acting on ribonucleic acid (ADAR). APOBECs induce C→U transitions in viral genomes; the APOBEC locus is highly polymorphic with variable numbers of APOBEC3 paralogs and target preferences in humans and other mammals. APOBEC3 paralogs have shaped the evolutionary history of human immunodeficiency virus, with compelling bioinformatic evidence also for its mutagenic impact on monkeypox virus and severe acute respiratory syndrome coronavirus 2. ADAR-1 induces adenose-to-inosine (A→I) substitutions in double-stranded ribonucleic acid (RNA); its role in virus adaptation is less clear, as are epigenetic modifications to viral genomes, such as methylation. Nucleic acid editing restricts evolutionary space in which viruses can explore and may restrict viral-host range.
    MeSH term(s) Animals ; Humans ; Nucleic Acids ; COVID-19 ; Viruses/genetics ; Mammals ; RNA
    Chemical Substances Nucleic Acids ; RNA (63231-63-0)
    Language English
    Publishing date 2023-04-07
    Publishing country Netherlands
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2611378-8
    ISSN 1879-6265 ; 1879-6257
    ISSN (online) 1879-6265
    ISSN 1879-6257
    DOI 10.1016/j.coviro.2023.101326
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  2. Article ; Online: Rampant C->U hypermutation in the genomes of SARS-CoV-2 and other coronaviruses – causes and consequences for their short and long evolutionary trajectories

    Simmonds, Peter

    bioRxiv

    Abstract: The pandemic of SARS coronavirus 2 (SARS-CoV-2) has motivated an intensive analysis of its molecular epidemiology following its worldwide spread. To understand the early evolutionary events following its emergence, a dataset of 985 complete SARS-CoV-2 ... ...

    Abstract The pandemic of SARS coronavirus 2 (SARS-CoV-2) has motivated an intensive analysis of its molecular epidemiology following its worldwide spread. To understand the early evolutionary events following its emergence, a dataset of 985 complete SARS-CoV-2 sequences was assembled. Variants showed a mean 5.5-9.5 nucleotide differences from each other, commensurate with a mid-range coronavirus substitution rate of 3x10-4 substitutions/site/year. Almost half of sequence changes were C->U transitions with an 8-fold base frequency normalised directional asymmetry between C->U and U->C substitutions. Elevated ratios were observed in other recently emerged coronaviruses (SARS-CoV and MERS-CoV) and to a decreasing degree in other human coronaviruses (HCoV-NL63, OC43, 229E and HKU1) proportionate to their increasing divergence. C->U transitions underpinned almost half of the amino acid differences between SARS-CoV-2 variants, and occurred preferentially in both 59U/A and 39U/A flanking sequence contexts comparable to favoured motifs of human APOBEC3 proteins. Marked base asymmetries observed in non-pandemic human coronaviruses (U>>A>G>>C) and low G+C contents may represent long term effects of prolonged C->U hypermutation in their hosts. The evidence that much of sequence change in SARS-CoV-2 and other coronaviruses may be driven by a host APOBEC-like editing process has profound implications for understanding their short and long term evolution. Repeated cycles of mutation and reversion in favoured mutational hotspots and the widespread occurrence of amino acid changes with no adaptive value for the virus represents a quite different paradigm of virus sequence change from neutral and Darwinian evolutionary frameworks that are typically used in molecular epidemiology investigations.
    Keywords covid19
    Language English
    Publishing date 2020-05-01
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2020.05.01.072330
    Database COVID19

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  3. Article ; Online: Pervasive RNA secondary structure in the genomes of SARS-CoV-2 and other coronaviruses – an endeavour to understand its biological purpose

    Simmonds, Peter

    bioRxiv

    Abstract: The ultimate outcome of the COVID-19 pandemic is unknown and is dependent on a complex interplay of its pathogenicity, transmissibility and population immunity. In the current study, the SARS coronavirus 2 (SARS-CoV-2) genome was investigated for the ... ...

    Abstract The ultimate outcome of the COVID-19 pandemic is unknown and is dependent on a complex interplay of its pathogenicity, transmissibility and population immunity. In the current study, the SARS coronavirus 2 (SARS-CoV-2) genome was investigated for the presence of large scale internal RNA base pairing in its genome. This property, termed genome scale ordered RNA structure (GORS) has been previously associated with host persistence in other +strand RNA viruses, potentially through its shielding effect on viral RNA recognition in the cell. Genomes of SARS-CoV-2 were remarkably structured, with minimum folding energy differences (MFEDs) of 15%, substantially greater than previously examined viruses such as HCV (MFED 7-9%). High MFED values were shared with all coronavirus genomes analysed created by several hundred consecutive energetically favoured stem-loops throughout the genome. In contrast to replication-association RNA structure, GORS was poorly conserved in the positions and identities of base pairing with other sarbecoviruses - even similarly positioned stem-loops in SARS-CoV-2 and SARS-CoV rarely shared homologous pairings, indicative of more rapid evolutionary change in RNA structure than in the underlying coding sequences. Sites predicted to be base-paired in SARS-CoV-2 showed substantially less sequence diversity than unpaired sites, suggesting that disruption of RNA structure by mutation imposes a fitness cost on the virus which is potentially restrictive to its longer evolution. Although functionally uncharacterised, GORS in SARS-CoV-2 and other coronaviruses represent important elements in their cellular interactions that may contribute to their persistence and transmissibility.
    Keywords covid19
    Language English
    Publishing date 2020-06-17
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2020.06.17.155200
    Database COVID19

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  4. Article ; Online: A clash of ideas - the varying uses of the 'species' term in virology and their utility for classifying viruses in metagenomic datasets.

    Simmonds, Peter

    The Journal of general virology

    2018  Volume 99, Issue 3, Page(s) 277–287

    Abstract: Species definitions of viruses are frequently descriptive, with assignments often being based on their disease manifestations, host range, geographical distribution and transmission routes. This method of categorizing viruses has recently been challenged ...

    Abstract Species definitions of viruses are frequently descriptive, with assignments often being based on their disease manifestations, host range, geographical distribution and transmission routes. This method of categorizing viruses has recently been challenged by technology advances, such as high-throughput sequencing. These have dramatically increased knowledge of viral diversity in the wider environment that dwarfs the current catalogue of viruses classified by the International Committee for the Taxonomy of Viruses (ICTV). However, because such viruses are known only from their sequences without phenotypic information, it is unclear how they might be classified consistently with much of the existing taxonomy framework. This difficulty exposes deeper incompatibilities in how species are conceptualized. The original species assignments based on disease or other biological attributes were primarily descriptive, similar to principles used elsewhere in biology for species taxonomies. In contrast, purely sequence-based classifications rely on genetic metrics such as divergence thresholds that include or exclude viruses in individual species categories. These different approaches bring different preconceptions about the nature of a virus species, the former being more easily conceptualized as a category with a part/whole relationship of individuals and species, while species defined by divergence thresholds or other genetic metrics are essentially logically defined groups with specific inclusion and exclusion criteria. While descriptive species definitions match our intuitive division of viruses into natural kinds, rules-based genetic classifications are required for viruses known from sequence alone, whose incorporation into the ICTV taxonomy is essential if it is to represent the true diversity of viruses in nature.
    Language English
    Publishing date 2018-01-12
    Publishing country England
    Document type Journal Article
    ZDB-ID 219316-4
    ISSN 1465-2099 ; 0022-1317
    ISSN (online) 1465-2099
    ISSN 0022-1317
    DOI 10.1099/jgv.0.001010
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  5. Article ; Online: Evaluating the risk of transfusion and transplant-transmitted monkeypox infections.

    Harvala, Heli / Simmonds, Peter

    Transfusion medicine (Oxford, England)

    2022  Volume 32, Issue 6, Page(s) 460–466

    Abstract: The recent emergence of monkeypox virus (MPXV) in the UK and elsewhere is of urgent public health concern. Several aspects of MPXV epidemiology and pathogenesis, including its systemic spread and viraemia during acute infection, furthermore represent an ... ...

    Abstract The recent emergence of monkeypox virus (MPXV) in the UK and elsewhere is of urgent public health concern. Several aspects of MPXV epidemiology and pathogenesis, including its systemic spread and viraemia during acute infection, furthermore represent an important potential threat to the safety of blood transfusion and organ transplantation. Reported infections in the UK have been exponentially increasing over the last 2 months, with 1552 reported cases in the UK by 7th July 2022. This is likely to be considerable underestimate given current limitations in diagnostic capacity and clinical diagnoses hampered by its similar disease presentations to other causes of rash and genitourinary disease. While MPXV infections are currently most widespread in gay, bisexual or other men who have sex with men, wider spread of MPXV outside defined risk groups for infection may prevent identification of infection risk in donors. While typically mild disease outcomes have been reported in UK cases, case fatality rates ranging from 1% to over 10% are reported for different MPXV strains in its source area in sub-Saharan Africa. Recipients of blood components and organs transplant, especially those who are immunosuppressed, may reproduce the greater systemic spread and morbidity of those infected through percutaneous routes. There is a potential risk of MPXV transmission and severe disease outcomes in blood and transplant recipients. In addition to current risk assessments performed in the UK and exclusion of donors with recent MPXV exposure, determining viraemia frequencies in donors and directly evaluating transmission risk would be of considerable value in assessing whether MPXV nucleic acid screening should be implemented.
    MeSH term(s) Male ; Humans ; Mpox (monkeypox)/diagnosis ; Viremia ; Homosexuality, Male ; Sexual and Gender Minorities ; Monkeypox virus ; Blood Transfusion
    Language English
    Publishing date 2022-09-22
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1067989-3
    ISSN 1365-3148 ; 0958-7578
    ISSN (online) 1365-3148
    ISSN 0958-7578
    DOI 10.1111/tme.12918
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3177: Show issues Location:
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  6. Article ; Online: Biomarkers of transfusion transmitted occult hepatitis B virus infection: Where are we and what next?

    Fu, Michael X / Simmonds, Peter / Andersson, Monique / Harvala, Heli

    Reviews in medical virology

    2024  Volume 34, Issue 2, Page(s) e2525

    Abstract: Blood transfusion is a vital procedure, where transfusion-transmitted infection of hepatitis B virus (HBV) remains an important issue, especially from blood donors with occult hepatitis B virus infection (OBI). Occult hepatitis B virus infection is a ... ...

    Abstract Blood transfusion is a vital procedure, where transfusion-transmitted infection of hepatitis B virus (HBV) remains an important issue, especially from blood donors with occult hepatitis B virus infection (OBI). Occult hepatitis B virus infection is a complex entity to detect using surrogate blood biomarkers for intrahepatic viral transcriptional activity, requiring a continually refined battery of tests utilised for screening. This review aims to critically evaluate the latest advances in the current blood biomarkers to guide the identification of OBI donors and discuss novel HBV markers that could be introduced in future diagnostic practice. Challenges in detecting low HBV surface antigen levels, mutants, and complexes necessitate ultrasensitive multivalent dissociation assays, whilst HBV DNA testing requires improved sensitivity but worsens inaccessibility. Anti-core antibody assays defer almost all potentially infectious donations but have low specificity, and titres of anti-surface antibodies that prevent infectivity are poorly defined with suboptimal sensitivity. The challenges associated with these traditional blood HBV markers create an urgent need for alternative biomarkers that would help us better understand the OBI. Emerging viral biomarkers, such as pre-genomic RNA and HBV core-related antigen, immunological HBV biomarkers of T-cell reactivity and cytokine levels, and host biomarkers of microRNA and human leucocyte antigen molecules, present potential advances to gauge intrahepatic activity more accurately. Further studies on these markers may uncover an optimal diagnostic algorithm for OBI using quantification of various novel and traditional blood HBV markers. Addressing critical knowledge gaps identified in this review would decrease the residual risk of transfusion-transmitted HBV infection without compromising the sustainability of blood supplies.
    MeSH term(s) Humans ; Hepatitis B virus/genetics ; Hepatitis B Antibodies ; Hepatitis B ; Hepatitis B, Chronic ; Blood Transfusion ; Hepatitis B Core Antigens ; Blood Donors ; Biomarkers ; DNA, Viral
    Chemical Substances Hepatitis B Antibodies ; Hepatitis B Core Antigens ; Biomarkers ; DNA, Viral
    Language English
    Publishing date 2024-02-20
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1086043-5
    ISSN 1099-1654 ; 1052-9276
    ISSN (online) 1099-1654
    ISSN 1052-9276
    DOI 10.1002/rmv.2525
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3308: Show issues Location:
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  7. Article ; Online: Extensive C->U transition biases in the genomes of a wide range of mammalian RNA viruses; potential associations with transcriptional mutations, damage- or host-mediated editing of viral RNA.

    Simmonds, Peter / Ansari, M Azim

    PLoS pathogens

    2021  Volume 17, Issue 6, Page(s) e1009596

    Abstract: The rapid evolution of RNA viruses has been long considered to result from a combination of high copying error frequencies during RNA replication, short generation times and the consequent extensive fixation of neutral or adaptive changes over short ... ...

    Abstract The rapid evolution of RNA viruses has been long considered to result from a combination of high copying error frequencies during RNA replication, short generation times and the consequent extensive fixation of neutral or adaptive changes over short periods. While both the identities and sites of mutations are typically modelled as being random, recent investigations of sequence diversity of SARS coronavirus 2 (SARS-CoV-2) have identified a preponderance of C->U transitions, proposed to be driven by an APOBEC-like RNA editing process. The current study investigated whether this phenomenon could be observed in datasets of other RNA viruses. Using a 5% divergence filter to infer directionality, 18 from 36 datasets of aligned coding region sequences from a diverse range of mammalian RNA viruses (including Picornaviridae, Flaviviridae, Matonaviridae, Caliciviridae and Coronaviridae) showed a >2-fold base composition normalised excess of C->U transitions compared to U->C (range 2.1x-7.5x), with a consistently observed favoured 5' U upstream context. The presence of genome scale RNA secondary structure (GORS) was the only other genomic or structural parameter significantly associated with C->U/U->C transition asymmetries by multivariable analysis (ANOVA), potentially reflecting RNA structure dependence of sites targeted for C->U mutations. Using the association index metric, C->U changes were specifically over-represented at phylogenetically uninformative sites, potentially paralleling extensive homoplasy of this transition reported in SARS-CoV-2. Although mechanisms remain to be functionally characterised, excess C->U substitutions accounted for 11-14% of standing sequence variability of structured viruses and may therefore represent a potent driver of their sequence diversification and longer-term evolution.
    MeSH term(s) APOBEC Deaminases/metabolism ; Animals ; Base Sequence ; COVID-19/virology ; Cytidine/genetics ; DNA Damage/physiology ; Evolution, Molecular ; Gene Expression Regulation, Viral ; Genome, Viral ; Host-Pathogen Interactions/genetics ; Humans ; Mammals/virology ; Mutation ; Nucleic Acid Conformation ; Phylogeny ; RNA Editing/physiology ; RNA Viruses/classification ; RNA Viruses/genetics ; RNA, Viral/chemistry ; RNA, Viral/genetics ; SARS-CoV-2/chemistry ; SARS-CoV-2/classification ; SARS-CoV-2/genetics ; Sequence Analysis, RNA ; Transcription, Genetic/genetics ; Uridine/genetics
    Chemical Substances RNA, Viral ; Cytidine (5CSZ8459RP) ; APOBEC Deaminases (EC 3.5.4.5) ; Uridine (WHI7HQ7H85)
    Language English
    Publishing date 2021-06-01
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7374
    ISSN (online) 1553-7374
    ISSN 1553-7374
    DOI 10.1371/journal.ppat.1009596
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  8. Article ; Online: Potential APOBEC-mediated RNA editing of the genomes of SARS-CoV-2 and other coronaviruses and its impact on their longer term evolution.

    Ratcliff, Jeremy / Simmonds, Peter

    Virology

    2021  Volume 556, Page(s) 62–72

    Abstract: 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. ... ...

    Abstract 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.
    MeSH term(s) APOBEC Deaminases/chemistry ; APOBEC Deaminases/genetics ; APOBEC Deaminases/metabolism ; Animals ; Coronavirus/genetics ; Coronavirus Infections/virology ; Evolution, Molecular ; Genome, Viral/genetics ; Humans ; Mutation ; RNA Editing ; SARS-CoV-2/genetics
    Chemical Substances APOBEC Deaminases (EC 3.5.4.5)
    Language English
    Publishing date 2021-01-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 200425-2
    ISSN 1096-0341 ; 0042-6822
    ISSN (online) 1096-0341
    ISSN 0042-6822
    DOI 10.1016/j.virol.2020.12.018
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  9. Article: Potential APOBEC-mediated RNA editing of the genomes of SARS-CoV-2 and other coronaviruses and its impact on their longer term evolution

    Ratcliff, Jeremy / Simmonds, Peter

    Virology. 2021 Apr., v. 556

    2021  

    Abstract: 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. ... ...

    Abstract 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.
    Keywords Coronavirus infections ; Herpesviridae ; Human coronavirus NL63 ; RNA ; RNA editing ; Retroviridae ; amino acid sequences ; antiviral properties ; cells ; cytidine deaminase ; evolution ; gene editing ; genome ; genomics ; knowledge ; mammals ; nucleotide sequences ; occurrence ; pandemic ; viral proteins ; virology
    Language English
    Dates of publication 2021-04
    Size p. 62-72.
    Publishing place Elsevier Inc.
    Document type Article
    Note NAL-light
    ZDB-ID 200425-2
    ISSN 1096-0341 ; 0042-6822
    ISSN (online) 1096-0341
    ISSN 0042-6822
    DOI 10.1016/j.virol.2020.12.018
    Database NAL-Catalogue (AGRICOLA)

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  10. Article ; Online: Parechovirus A Circulation and Testing Capacities in Europe, 2015-2021.

    Bubba, Laura / Broberg, Eeva K / Fischer, Thea K / Simmonds, Peter / Harvala, Heli

    Emerging infectious diseases

    2024  Volume 30, Issue 2, Page(s) 234–244

    Abstract: Parechovirus infections usually affect neonates and young children; manifestations vary from asymptomatic to life-threatening. We describe laboratory capacity in Europe for assessing parechovirus circulation, seasonality, and epidemiology. We used ... ...

    Abstract Parechovirus infections usually affect neonates and young children; manifestations vary from asymptomatic to life-threatening. We describe laboratory capacity in Europe for assessing parechovirus circulation, seasonality, and epidemiology. We used retrospective anonymized data collected from parechovirus infection case-patients identified in Europe during January 2015-December 2021. Of 21 laboratories from 18 countries that participated in the study, 16 (76%) laboratories with parechovirus detection capacity reported 1,845 positive samples; 12/16 (75%) with typing capability successfully identified 517 samples. Parechovirus A3 was the most common type (n = 278), followed by A1 (153), A6 (50), A4 (13), A5 (22), and A14 (1). Clinical data from 1,269 participants highlighted correlation of types A3, A4, and A5 with severe disease in neonates. We observed a wide capacity in Europe to detect, type, and analyze parechovirus data. To enhance surveillance and response for PeV outbreaks, sharing typing protocols and data on parechovirus-positive cases should be encouraged.
    MeSH term(s) Child ; Infant, Newborn ; Humans ; Child, Preschool ; Parechovirus/genetics ; Retrospective Studies ; Europe/epidemiology ; Disease Outbreaks ; Laboratories
    Language English
    Publishing date 2024-01-25
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 1380686-5
    ISSN 1080-6059 ; 1080-6040
    ISSN (online) 1080-6059
    ISSN 1080-6040
    DOI 10.3201/eid3002.230647
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