DOCSLIB.ORG

Different Within-Host Viral Evolution Dynamics in Severely Immunosuppressed Cases with Persistent SARS-Cov-2

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Different Within-Host Viral Evolution Dynamics in Severely Immunosuppressed Cases with Persistent SARS-Cov-2 biomedicines Article Different Within-Host Viral Evolution Dynamics in Severely Immunosuppressed Cases with Persistent SARS-CoV-2 Laura Pérez-Lago 1,2,† , Teresa Aldámiz-Echevarría 1,2,†, Rita García-Martínez 2,3,† , Leire Pérez-Latorre 1,2,†, Marta Herranz 1,2,4, Pedro J. Sola-Campoy 1,2, Julia Suárez-González 2,5, Carolina Martínez-Laperche 2,6, Iñaki Comas 7,8, Fernando González-Candelas 8,9 , Pilar Catalán 1,2,4, Patricia Muñoz 1,2,4,10 , Darío García de Viedma 1,2,4,* and on behalf of Gregorio Marañón Microbiology-ID COVID 19 Study Group ‡ 1 Clinical Microbiology and Infectious Diseases Department, Gregorio Marañón General University Hospital, 28007 Madrid, Spain; [email protected] (L.P.-L.); [email protected] (T.A.-E.); [email protected] (L.P.-L.); [email protected] (M.H.); [email protected] (P.J.S.-C.); [email protected] (P.C.); [email protected] (P.M.) 2 Gregorio Marañón Health Research Institute (IiSGM), 28007 Madrid, Spain; [email protected] (R.G.-M.); [email protected] (J.S.-G.); [email protected] (C.M.-L.) 3 Internal Medicine Department, Gregorio Marañón General University Hospital, 28007 Madrid, Spain 4 CIBER Respiratory Diseases (CIBERES), 28029 Madrid, Spain 5 Genomics Unit, Gregorio Marañón General University Hospital, 28007 Madrid, Spain 6 Oncohematology Service, Gregorio Marañón General University Hospital, 28007 Madrid, Spain 7 Tuberculosis Genomics Unit, Instituto de Biomedicina de Valencia-CSIC, 46010 Valencia, Spain; [email protected] Citation: Pérez-Lago, L.; 8 CIBER Salud Pública (CIBERESP), 28029 Madrid, Spain; [email protected] 9 Aldámiz-Echevarría, T.; Joint Research Unit “Infection and Public Health”, Institute for Integrative Systems Biology (I2SysBio), García-Martínez, R.; Pérez-Latorre, L.; FISABIO-University of Valencia, 46980 Valencia, Spain 10 Departamento de Medicina, Universidad Complutense, 28040 Madrid, Spain Herranz, M.; Sola-Campoy, P.J.; * Correspondence: [email protected]; Tel.: +34-914265104 Suárez-González, J.; Martínez-Laperche, † These authors contributed equally to this work. The order of the author was determined by agreement C.; Comas, I.; González-Candelas, F.; between the authors. et al. Different Within-Host Viral ‡ On behalf of the Gregorio Marañón’s Microbiology-ID COVID 19 Study Group members are provided in the Evolution Dynamics in Severely Acknowledgments. Immunosuppressed Cases with Persistent SARS-CoV-2. Biomedicines Abstract: A successful Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant, 2021, 9, 808. https://doi.org/ B.1.1.7, has recently been reported in the UK, causing global alarm. Most likely, the new variant 10.3390/biomedicines9070808 emerged in a persistently infected patient, justifying a special focus on these cases. Our aim in this study was to explore certain clinical profiles involving severe immunosuppression that may help Academic Editor: Marjorie Pion explain the prolonged persistence of viable viruses. We present three severely immunosuppressed cases (A, B, and C) with a history of lymphoma and prolonged SARS-CoV-2 shedding (2, 4, and Received: 22 May 2021 Accepted: 7 July 2021 6 months), two of whom finally died. Whole-genome sequencing of 9 and 10 specimens from Cases Published: 13 July 2021 A and B revealed extensive within-patient acquisition of diversity, 12 and 28 new single nucleotide polymorphisms, respectively, which suggests ongoing SARS-CoV-2 replication. This diversity was Publisher’s Note: MDPI stays neutral not observed for Case C after analysing 5 sequential nasopharyngeal specimens and one plasma with regard to jurisdictional claims in specimen, and was only observed in one bronchoaspirate specimen, although viral viability was published maps and institutional affil- still considered based on constant low Ct values throughout the disease and recovery of the virus iations. in cell cultures. The acquired viral diversity in Cases A and B followed different dynamics. For Case A, new single nucleotide polymorphisms were quickly fixed (13–15 days) after emerging as minority variants, while for Case B, higher diversity was observed at a slower emergence: fixation pace (1–2 months). Slower SARS-CoV-2 evolutionary pace was observed for Case A following the Copyright: © 2021 by the authors. administration of hyperimmune plasma. This work adds knowledge on SARS-CoV-2 prolonged Licensee MDPI, Basel, Switzerland. shedding in severely immunocompromised patients and demonstrates viral viability, noteworthy This article is an open access article acquired intra-patient diversity, and different SARS-CoV-2 evolutionary dynamics in persistent cases. distributed under the terms and conditions of the Creative Commons Keywords: COVID-19; SARS-CoV-2; persistence; immunosuppressed; diversity; viral viability; Attribution (CC BY) license (https:// genomics creativecommons.org/licenses/by/ 4.0/). Biomedicines 2021, 9, 808. https://doi.org/10.3390/biomedicines9070808 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, 808 2 of 12 1. Introduction A recent review [1] established that the mean duration of SARS-CoV-2 in upper respiratory tract viral shedding is 17 days, with a maximum of 83 days, although certain studies report SARS-CoV-2 positive RT-PCRs up to 101 days [2]. With the identification of prolonged persistence, it was necessary to clarify whether these cases were still infectious or if they corresponded to the presence of residual genomic RNA. The standard approach to assess viability has relied on cell cultures, and most studies fail to detect live viruses beyond Day 9 [1]. The detection of subgenomic viral RNA as a way to infer viral replication has been used as an alternative to cell cultures to assess viability [2]. The dynamics of SARS-CoV-2 are a balance between its replication and the host’s immune response to control it. Thus, immunocompromised patients may offer the virus better opportunities to persist. This subgroup of patients may constitute a suitable model to dissect the ability of SARS-CoV-2 to acquire intrapatient diversity, determine the magnitude of intrahost evolution, evaluate the potential role of acquired mutations, and extend our understanding on the dynamics of SARS-CoV-2 infection. Whole genome sequencing of SARS-CoV-2 is key to understand the global expansion of the virus [3], track current transmission dynamics [4] or outbreaks [5], and determine reinfections [6]. However, the genomic analysis has scarcely been applied to better un- derstand the evolutionary dynamics of SARS-CoV-2 along persistent infections [7–9]. The interest of understanding within-patient evolution of SARS-CoV-2 in prolonged infections has recently increased due to the identification of a successful variant in the UK, B.1.1.7, which has been hypothesized to have emerged from one persistently infected case [10]. In this study, we present a detailed clinical description of three severely immunocom- promised subjects with SARS-CoV-2 prolonged shedding, in-depth genomic viral analysis on multiple sequential specimens, and an assessment of viability in cell cultures. 2. Materials and Methods 2.1. Diagnostic RT-PCR RNA was extracted and purified from 300 µL of a nasopharyngeal exudate with the KingFisher (Thermo Fisher Scientific, Waltham, MA, USA), and the TaqPath COVID-19 CE-IVD RT-PCR (Thermo Fisher Scientific, Waltham, MA, USA) was applied. 2.2. Whole Genome Sequencing Viral sequencing was done using the Artic_nCov-2019_V3 panel of primers (Integrated DNA Technologies, Inc., Coralville, IA, USA) (artic.network/ncov-2019, 24 March 2020), and libraries were prepared using the Nextera Flex DNA Library Preparation Kit (Illumina lnc, San Diego, CA, USA) and sequenced on the Miseq system (Illumina Inc, San Diego, CA, USA). Details for WGS and bioinformatic analysis are specified in Supplementary Materials. Fasta files above the GISAID thresholds were deposited in GISAID (accession numbers in Supplementary Materials). The following frequencies were considered for variant calling: minority variants (MVs; frequency < 20%), intermediate variants (IVs; frequency 20–80%), and fixed single nucleotide polymorphisms (SNPs; frequency > 80%). 2.3. Short Tandem Repeat Analysis Human identity testing analysis was performed by short tandem repeat (STR) PCR (Mentype® Chimera® Biotype, Dresden, Germany) on the same specimens used to perform SARS-CoV-2 RT-PCRs and sequencing. Details are included in Supplementary Materials. 2.4. Cell Cultures For viral amplification, Vero E6 cells (ATCC CRL1586) were inoculated with positive SARS-CoV-2 samples. Details are included in Supplementary Materials. Cultures were considered positive when fulfilling at least one of the following criteria: (i) appearance of CPE, (ii) positive immunofluorescence detected, or (iii) a decrease of ≥3 Biomedicines 2021, 9, 808 3 of 12 (equivalent to a 1 log increase in virus quantity) between the Ct of the original sample and final culture supernatant. 2.5. Subgenomic RNA RNA remnants purified (KingFisher, Thermo Fisher Scientific, Waltham, MA, USA) from diagnostic nasopharyngeal swab specimens (300 µL of UTM swabs, COPAN, Biomerieux, Marcy-l’Étoile, France) were used as templates for the PCR design described elsewhere [11] for specific detection of the SG E gene RNA (+strand). 3. Results 3.1. Case A 3.1.1. Clinical Case A 52-year-old male with rituximab treatment every three months for a follicular lym- phoma in remission was admitted in June 2020. SARS-CoV-2 infection was diagnosed on 23 March (Day 0) 2020, a few days after receiving
Load more

Recommended publications
  • Mutational Load Causes Stochastic Evolutionary Outcomes In
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Apollo Virus Evolution, 2019, 5(1): vez008 doi: 10.1093/ve/vez008 Research article Mutational load causes stochastic evolutionary outcomes in acute RNA viral infection Downloaded from https://academic.oup.com/ve/article-abstract/5/1/vez008/5476199 by guest on 01 June 2020 Lei Zhao,1,† Ali B. Abbasi,1 and Christopher J. R. Illingworth1,2,*,‡ 1Department of Genetics, University of Cambridge, Cambridge, UK and 2Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK *Corresponding author: E-mail: [email protected] †http://orcid.org/0000-0002-6551-2707 ‡http://orcid.org/0000-0002-0030-2784 Abstract Mutational load is known to be of importance for the evolution of RNA viruses, the combination of a high mutation rate and large population size leading to an accumulation of deleterious mutations. However, while the effects of mutational load on global viral populations have been considered, its quantitative effects at the within-host scale of infection are less well un- derstood. We here show that even on the rapid timescale of acute disease, mutational load has an effect on within-host vi- ral adaptation, reducing the effective selection acting upon beneficial variants by 10 per cent. Furthermore, mutational load induces considerable stochasticity in the pattern of evolution, causing a more than five-fold uncertainty in the effective fitness of a transmitted beneficial variant. Our work aims to bridge the gap between classic models from population genetic theory and the biology of viral infection.
    [Show full text]
  • Changes in Population Dynamics in Mutualistic Versus Pathogenic Viruses
    Viruses 2011, 3, 12-19; doi:10.3390/v3010012 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Commentary Changes in Population Dynamics in Mutualistic versus Pathogenic Viruses Marilyn J. Roossinck Plant Biology Division, The Samuel Roberts Noble Foundation, Inc., P.O. Box 2180, Ardmore, OK 73402, USA; E-Mail: [email protected]; Tel.: +1 580 224 6600; Fax: +1 580 224 6692. Received: 17 December 2010; in revised form: 31 December 2010 / Accepted: 6 January 2011 / Published: 17 January 2011 Abstract: Although generally regarded as pathogens, viruses can also be mutualists. A number of examples of extreme mutualism (i.e., symbiogenesis) have been well studied. Other examples of mutualism are less common, but this is likely because viruses have rarely been thought of as having any beneficial effects on their hosts. The effect of mutualism on the population dynamics of viruses is a topic that has not been addressed experimentally. However, the potential for understanding mutualism and how a virus might become a mutualist may be elucidated by understanding these dynamics. Keywords: beneficial viruses; polymerase fidelity; quasispecies; symbiosis; symbiogenesis 1. Introduction Viruses have been studied predominantly as pathogens, beginning with the first virus ever described, Tobacco mosaic virus [1] that was causing spots on tobacco plants. However, a number of viruses in plants, animals, fungi and bacteria have been described that are not pathogens; many are commensals and some are mutualists. Traditionally, mutualistic symbioses are thought of as long-term stable relationships, but viruses can clearly switch lifestyles depending on conditions. What effect does mutualism have on the population dynamics of a virus? Do the population dynamics of conditional mutualists change depending on their lifestyle? This is the subject of this brief perspective.
    [Show full text]
  • Evolutionary Analysis of the Dynamics of Viral Infectious Disease
    REVIEWS MODELLING Evolutionary analysis of the dynamics of viral infectious disease Oliver G. Pybus* and Andrew Rambaut‡ Abstract | Many organisms that cause infectious diseases, particularly RNA viruses, mutate so rapidly that their evolutionary and ecological behaviours are inextricably linked. Consequently, aspects of the transmission and epidemiology of these pathogens are imprinted on the genetic diversity of their genomes. Large-scale empirical analyses of the evolutionary dynamics of important pathogens are now feasible owing to the increasing availability of pathogen sequence data and the development of new computational and statistical methods of analysis. In this Review, we outline the questions that can be answered using viral evolutionary analysis across a wide range of biological scales. REFS 5–7 Balancing selection Rapidly evolving pathogens are unique in that their key human pathogens (for example, ). Any form of natural selection ecological and evolutionary dynamics occur on the Understandably, most studies have focused on impor- that results in the maintenance same timescale and can therefore potentially interact. tant human RNA viruses such as influenza virus, HIV, of genetic polymorphisms in a For example, the exceptionally high nucleotide mutation dengue virus and hepatitis C virus (HCV); therefore, this population, as opposed to 1 their loss through fixation or rate of a typical RNA virus — a million times greater Review concentrates on these infections. However, the elimination. than that of vertebrates — allows these viruses to gener- range of pathogens and hosts to which phylodynamic ate mutations and adaptations de novo during environ- methods are applied is expanding, and we also discuss mental change, whereas other organisms must rely on infectious diseases of wildlife, crops and livestock.
    [Show full text]
  • Viral Host-Adaptation : Insights from Evolution Experiments with Phages
    This is a repository copy of Viral host-adaptation : insights from evolution experiments with phages. White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/77996/ Version: Submitted Version Article: Hall, James Pj, Harrison, Ellie and Brockhurst, Michael A orcid.org/0000-0003-0362-820X (2013) Viral host-adaptation : insights from evolution experiments with phages. Current Opinion in Virology. pp. 572-577. ISSN 1879-6265 https://doi.org/10.1016/j.coviro.2013.07.001 Reuse Items deposited in White Rose Research Online are protected by copyright, with all rights reserved unless indicated otherwise. They may be downloaded and/or printed for private study, or other acts as permitted by national copyright laws. The publisher or other rights holders may allow further reproduction and re-use of the full text version. This is indicated by the licence information on the White Rose Research Online record for the item. Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ 1 Viral host-adaptation: insights from evolution experiments with phages 2 James P. J. Hall, Ellie Harrison, Michael A. Brockhurst 3 Department of Biology, University of York, Wentworth Way, York YO10 5DD 4 5 Author for correspondence: 6 Professor Michael A. Brockhurst 7 Postal address: Department of Biology, University of York, Wentworth Way, York YO10 8 5DD 9 Telephone: 00 44 1904 328 576 10 Email: [email protected] 11 12 Abstract 13 Phages, viral parasites of bacteria, share fundamental features of pathogenic animal and 14 plant viruses and represent a highly tractable empirical model system to understand viral 15 evolution and in particular viral host-adaptation.
    [Show full text]
  • 1 Chapter I Overall Issues of Virus and Host Evolution
    CHAPTER I OVERALL ISSUES OF VIRUS AND HOST EVOLUTION tree of life. Yet viruses do have the This book seeks to present the evolution of characteristics of life, can be killed, can become viruses from the perspective of the evolution extinct and adhere to the rules of evolutionary of their host. Since viruses essentially infect biology and Darwinian selection. In addition, all life forms, the book will broadly cover all viruses have enormous impact on the evolution life. Such an organization of the virus of their host. Viruses are ancient life forms, their literature will thus differ considerably from numbers are vast and their role in the fabric of the usual pattern of presenting viruses life is fundamental and unending. They according to either the virus type or the type represent the leading edge of evolution of all of host disease they are associated with. In living entities and they must no longer be left out so doing, it presents the broad patterns of the of the tree of life. evolution of life and evaluates the role of viruses in host evolution as well as the role Definitions. The concept of a virus has old of host in virus evolution. This book also origins, yet our modern understanding or seeks to broadly consider and present the definition of a virus is relatively recent and role of persistent viruses in evolution. directly associated with our unraveling the nature Although we have come to realize that viral of genes and nucleic acids in biological systems. persistence is indeed a common relationship As it will be important to avoid the perpetuation between virus and host, it is usually of some of the vague and sometimes inaccurate considered as a variation of a host infection views of viruses, below we present some pattern and not the basis from which to definitions that apply to modern virology.
    [Show full text]
  • Evolutionary Virology at 40
    | PERSPECTIVES Evolutionary Virology at 40 Jemma L. Geoghegan* and Edward C. Holmes†,‡,§,**,1 *Department of Biological Sciences, Macquarie University, Sydney, New South Wales 2109, Australia and †Marie Bashir Institute for Infectious Diseases and Biosecurity, ‡Charles Perkins Centre, §School of Life and Environmental Sciences, and **Sydney Medical School, The University of Sydney, New South Wales 2006, Australia ORCID IDs: 0000-0003-0970-0153 (J.L.G.); 0000-0001-9596-3552 (E.C.H.) ABSTRACT RNA viruses are diverse, abundant, and rapidly evolving. Genetic data have been generated from virus populations since the late 1970s and used to understand their evolution, emergence, and spread, culminating in the generation and analysis of many thousands of viral genome sequences. Despite this wealth of data, evolutionary genetics has played a surprisingly small role in our understanding of virus evolution. Instead, studies of RNA virus evolution have been dominated by two very different perspectives, the experimental and the comparative, that have largely been conducted independently and sometimes antagonistically. Here, we review the insights that these two approaches have provided over the last 40 years. We show that experimental approaches using in vitro and in vivo laboratory models are largely focused on short-term intrahost evolutionary mechanisms, and may not always be relevant to natural systems. In contrast, the comparative approach relies on the phylogenetic analysis of natural virus populations, usually considering data collected over multiple cycles of virus–host transmission, but is divorced from the causative evolutionary processes. To truly understand RNA virus evolution it is necessary to meld experimental and comparative approaches within a single evolutionary genetic framework, and to link viral evolution at the intrahost scale with that which occurs over both epidemiological and geological timescales.
    [Show full text]
  • The Evolution of Life History Trade-Offs in Viruses
    Available online at www.sciencedirect.com ScienceDirect The evolution of life history trade-offs in viruses Daniel H Goldhill and Paul E Turner Viruses can suffer ‘life-history’ trade-offs that prevent of trade-offs due to expected pleiotropy (single genes coding simultaneous improvement in fitness traits, such as improved for multiple proteins) and multifunctional proteins that play intrahost reproduction at the expense of reduced extrahost different roles during the viral lifecycle [7]. Viruses tend to survival. Here we examine reproduction-survival trade-offs and have short generation times, large population sizes and ease other trait compromises, highlighting that experimental of culture, allowing efficient experimental evolution studies evolution can reveal trade-offs and their associated that examine life history trade-offs [7]. Whole-genome se- mechanisms. Whereas ‘curse of the pharaoh’ (high virulence quencing easily permits identification of mutations changing with extreme stability) may generally apply for viruses of life history traits, in genome comparisons between ancestral eukaryotes, we suggest phages are instead likely to suffer and evolved viruses. Last, viral protein changes can reveal virulence/stability trade-offs. We examine how survival/ fundamental constraints and biophysical mechanisms of life reproduction trade-offs in viruses are affected by history trade-offs. environmental stressors, proteins governing viral host range, and organization of the virus genome. Future studies In addition, because viruses are exceedingly common on incorporating comparative biology, experimental evolution, earth and affect other organisms in myriad ways [8], and structural biology, could thoroughly determine how viral studying their life history trade-offs illuminates processes trade-offs evolve, and whether they transiently or permanently of global significance.
    [Show full text]
  • Modeling of Mutational Events in the Evolution of Viruses
    viruses Article Modeling of Mutational Events in the Evolution of Viruses Akhtar Ali 1 and Ulrich Melcher 2,* 1 Department of Biological Sciences, University of Tulsa, Tulsa, OK 74104, USA; [email protected] 2 Department of Biochemistry & Molecular Biology, Oklahoma State University, Stillwater, OK 74078-3035, USA * Correspondence: [email protected]; Tel.: +1-405-744-6210 Received: 4 March 2019; Accepted: 2 May 2019; Published: 5 May 2019 Abstract: Diverse studies of viral evolution have led to the recognition that the evolutionary rates of viral taxa observed are dependent on the time scale being investigated—with short-term studies giving fast substitution rates, and orders of magnitude lower rates for deep calibrations. Although each of these factors may contribute to this time dependent rate phenomenon, a more fundamental cause should be considered. We sought to test computationally whether the basic phenomena of virus evolution (mutation, replication, and selection) can explain the relationships between the evolutionary and phylogenetic distances. We tested, by computational inference, the hypothesis that the phylogenetic distances between the pairs of sequences are functions of the evolutionary path lengths between them. A Basic simulation revealed that the relationship between simulated genetic and mutational distances is non-linear, and can be consistent with different rates of nucleotide substitution at different depths of branches in phylogenetic trees. Keywords: virus–host co-divergence; endogenous viral elements; virus networks; speciation 1. Virus Evolution Introduction Viruses are often thought of as agents that have evolved to threaten humans and other manifestations of life. This view is strengthened by the impression that many disease epidemics (of humans, other animals, and plants) are of viral instigation.
    [Show full text]
  • Evolution of Viral Genomes - Interplay Between Selection, Recombination and Other Forces
    Evolution of viral genomes - Interplay between selection, recombination and other forces Sergei L. Kosakovsky Pond1, Ben Murrell2;3, and Art F. Y. Poon4 1 Department of Medicine, University of California, San Diego, USA 2 Computer Science Division, Department of Mathematical Sciences, University of Stellenbosch, Stellenbosch, South Africa 3 Biomedical Informatics Research Division, eHealth Research and Innovation Platform, Medical Research Council, Tygerberg, South Africa 4 BC Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada 1.1 Abstract RNA viruses evolve very rapidly, often recombine and are subject to strong host (immune response) and an- thropogenic (antiretroviral drugs) selective forces. Given their compact and extensively sequenced genomes, comparative analysis of RNA viral data can provide important insights into the molecular mechanisms of adaptation, pathogencity, immune evasion and drug resistance. In this chapter we present an example-based overview of recent advances in evolutionary models and statistical approaches that enable screening viral alignments for evidence of adaptive change in the presence of recombination, detecting bursts of directional adaptive evolution associated with the phenotypic changes, and detection of co-evolving sites in viral genes. 1 2 Keywords: viral evolution, recombination, natural selection, epistasis, machine learning, Bayesian networks. 1.2 Introduction Whether one considers them to be living organisms or not, viruses are the most extensively se- quenced members of the natural world. Virus genomes, especially those of RNA viruses, present many unique challenges to genetic sequence analysis. Even though they are comparably small in size (ranging approximately from 103 to 106 nucleotides in length) and contain a relatively small number of genes, they also undergo a very high mutation rate that drives the accumulation of ex- tensive sequence variation (9).
    [Show full text]
  • Viral Evolution: Accordion Adaptations Go Viral
    RESEARCH HIGHLIGHTS Nature Reviews Microbiology | AOP, published online 10 September 2012; doi:10.1038/nrmicro2883 therefore viral replication. Vaccinia Although a higher gene copy virus, a Poxviridae member, has two number can be beneficial in the short Macmillan antagonists for PKR known as K3L term, in the long term the increased and E3L, which differ in their ability genome size would probably incur a to target PKR variants in different host substantial fitness cost. It is perhaps species. However, as PKR is antago- not a surprise, therefore, that in nized by a wide range of viruses, the viruses passaged ten times, 3–12% of protein undergoes rapid evolution, the sequenced K3L genes contained raising the question of how vaccinia a mutation that resulted in a single virus and its two PKR antagonists can amino acid substitution (His47Arg) keep up despite the low viral mutation which had been identified in a previ- rate. To investigate this problem, Elde ous genetic screen for K3L mutants et al. made use of the fact that K3L is with enhanced activity against a poor antagonist of human PKR; by human PKR. Importantly, in those propagating a strain of vaccinia virus viral genomes that had only a single lacking E3L (ΔE3L) in HeLa cells, they copy of K3L after ten passages, the could place a strong selective pressure frequency of the His47Arg mutation on K3L to adapt. The authors found had increased to 47%, suggesting that the ΔE3L virus initially replicated that there was a strong selective much more slowly than wild-type pressure to ensure that the His47Arg virus in HeLa cells over 48 hours, but allele was maintained in viruses that after six passages the rate of rep- with reduced K3L copy numbers.
    [Show full text]
  • The Evolution of Epidemic Influenza
    REVIEWS The evolution of epidemic influenza Martha I. Nelson* and Edward C. Holmes*‡ Abstract | Recent developments in complete-genome sequencing, antigenic mapping and epidemiological modelling are greatly improving our knowledge of the evolution of human influenza virus at the epidemiological scale. In particular, recent studies have revealed a more complex relationship between antigenic evolution, natural selection and reassortment than previously realized. Despite these advances, there is much that remains to be understood about the epidemiology of influenza virus, particularly the processes that determine the virus’s strong seasonality. We argue that a complete understanding of the evolutionary biology of this important human pathogen will require a genomic view of genetic diversity, including the acquisition of polymorphism data from within individual hosts and from geographical regions, particularly the tropics, which have been poorly surveyed to date. Pandemic Influenza is one of the most important infectious diseases no onward transmission, as is currently the case with An epidemic that occurs over of humans. The annual mortality that is caused by influ- avian H5N1 influenza in humans; less frequently, they a large geographical area, enza in the United States alone is estimated at over 36,000 become established in new hosts, resulting in (irregular) including multiple countries. (REF. 1) (FIG. 1), whereas occasional global pandemics major human pandemics. can infect 20–40% of the population in a single year2. As Here we review our current understanding of the Epidemic The occurrence of more cases a notorious case in point, the pandemic of 1918–1919 evolutionary biology of human influenza A virus, show- than expected of an infectious caused possibly 20–50 million deaths on a global scale, ing how recent advances, particularly in comparative disease, in a defined making it the single most devastating disease outbreak genomics and epidemiology, have shed new light on geographical area over a in human history3.
    [Show full text]
  • An Interactive Viral Genome Evolution Network Analysis System Enabling
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.09.417121; this version posted December 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. An interactive viral genome evolution network analysis system enabling rapid large-scale molecular tracing of SARS-CoV-2 Yunchao Ling1,*, Ruifang Cao1,*, Jiaqiang Qian1,*, Jiefu Li1,2, Haokui Zhou4, Liyun Yuan1, Zhen Wang1, Guangyong Zheng1, Guoping Zhao1,3, Yixue Li1,2,#, Zefeng Wang1,2,#, Guoqing Zhang1,2,# 1 Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China 2 University of Chinese Academy of Sciences, Beijing, China 3 Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200031, China. 4 Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China * These authors contributed equally to this work # Corresponding to: [email protected]; [email protected]; [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.12.09.417121; this version posted December 10, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Comprehensive analyses of viral genomes can provide a global picture on SARS-CoV-2 transmission and help to predict the oncoming trends of pandemic.
    [Show full text]