Virus as Populations

Composition, Complexity, Dynamics, and Biological Implications
 
 
Academic Press
  • 1. Auflage
  • |
  • erschienen am 25. September 2015
  • |
  • 428 Seiten
 
E-Book | ePUB mit Adobe DRM | Systemvoraussetzungen
E-Book | PDF mit Adobe DRM | Systemvoraussetzungen
978-0-12-800994-9 (ISBN)
 
Virus as Populations: Composition, Complexity, Dynamics, and Biological Implications explains fundamental concepts that arise from regarding viruses as complex populations when replicating in infected hosts. Fundamental phenomena in virus behavior, such as adaptation to changing environments, capacity to produce disease, probability to be transmitted or response to treatment, depend on virus population numbers and in the variations of such population numbers. Concepts such as quasispecies dynamics, mutations rates, viral fitness, the effect of bottleneck events, population numbers in virus transmission and disease emergence, new antiviral strategies such as lethal mutagenesis, and extensions of population heterogeneity to nonviral systems are included. These main concepts of the book are framed in recent observations on general virus diversity derived from metagenomic studies, and current views on the origin of viruses and the role of viruses in the evolution of the biosphere.
  • Features current views on the key steps in the origin of life and origins of viruses
  • Includes examples relating ancestral features of viruses with their current adaptive capacity
  • Explains complex phenomena in an organized and coherent fashion that is easy to comprehend and enjoyable to read
  • Considers quasispecies as a framework to understand virus adaptability and disease processes


Esteban Domingo studied chemistry and biochemistry at the University of Barcelona, Spain and spent postdoctoral stays at the University of California, Irvine and the University of Zürich. His main interests are the quasispecies structure of RNA viruses and the development of new antiviral strategies. He is presently Professor of Research of the Spanish Research Council (CSIC) at Centro de Biología Molecular 'Servero Ochoa' in Madrid.
  • Englisch
  • USA
Elsevier Science
  • 35,98 MB
978-0-12-800994-9 (9780128009949)
0128009942 (0128009942)
weitere Ausgaben werden ermittelt
  • Front Cover
  • Virus as Populations: Composition, Complexity, Dynamics, and Biological Implications
  • Copyright
  • Contents
  • Foreword
  • Acknowledgments
  • Chapter 1: Introduction to Virus Origins and Their Role in Biological Evolution
  • 1.1 Considerations on Biological Diversity
  • 1.2 Some Questions of Current Virology and the Scope of This Book
  • 1.3 The Staggering Ubiquity and Diversity of Viruses: Limited Morphotypes
  • 1.4 Origin of Life: A Brief Historical Account and Current Views
  • 1.4.1 Early Synthesis of Oligonucleotides: A Possible Ancestral Positive Selection
  • 1.4.2 A Primitive RNA World
  • 1.4.3 Life from Mistakes, Information from Noninformation: Origin of Replicons
  • 1.4.4 Uptake of Energy and a Second Primitive Positive Selection
  • 1.5 Theories of the Origins of Viruses
  • 1.5.1 Viruses Are Remnants of Primeval Genetic Elements
  • 1.5.2 Viruses Are the Result of Regressive Microbial Evolution
  • 1.5.3 Viruses Are Liberated Autonomous Entities
  • 1.5.4 Viruses Are Elements for Long-Term Coevolution
  • 1.5.5 Viruses from Vesicles
  • 1.6 Being Alive Versus Being Part of Life
  • 1.7 Role of Viruses in the Evolution of the Biosphere
  • 1.7.1 Current Exchanges of Genetic Material
  • 1.7.2 Symbiotic Relationships
  • 1.8 Virus and Disease
  • 1.9 Overview and Concluding Remarks
  • References
  • Chapter 2: Molecular Basis of Genetic Variation of Viruses: Error-Prone Replication
  • 2.1 Universal Need of Genetic Variation
  • 2.2 Molecular Basis of Mutation
  • 2.3 Types and Effects of Mutations
  • 2.4 Inferences on Evolution Drawn from Mutation Types
  • 2.5 Mutation Rates and Frequencies for DNA and RNA Genomes
  • 2.6 Evolutionary Origins, Evolvability, and Consequences of High Mutation Rates: Fidelity Mutants
  • 2.7 Hypermutagenesis and Its Application to Generate Variation: APOBEC and ADAR Activities
  • 2.8 Error-Prone Replication and Maintenance of Genetic Information: Instability of Laboratory Viral Constructs
  • 2.9 Recombination in DNA and RNA Viruses
  • 2.9.1 Molecular Occurrence Versus Observed Recombination
  • 2.10 Genome Segment Reassortment
  • 2.11 Transition Toward Viral Genome Segmentation: Implications for General Evolution
  • 2.12 Mutation, Recombination, and Reassortment as Individual and Combined Evolutionary Forces
  • 2.13 Overview and Concluding Remarks
  • References
  • Chapter 3: Darwinian Principles Acting on Highly Mutable Viruses
  • 3.1 Theoretical Frameworks to Approach Virus Evolution
  • 3.1.1 Theory and Experiment
  • 3.2 Genetic Variation, Competition, and Selection
  • 3.3 Mutant Distributions During DNA and RNA Virus Infections
  • 3.4 Positive Versus Negative Selection: Two Sides of the Same Coin
  • 3.5 Selection and Random Drift
  • 3.6 Viral Quasispecies
  • 3.6.1 The Origins of Quasispecies Theory
  • 3.6.2 Deterministic Versus Stochastic Quasispecies
  • 3.6.3 Mutant Spectra, Master Genomes, and Consensus Sequences
  • 3.6.4 Measurement of Quasispecies Complexity: Insights from New Generation Sequencing
  • 3.6.5 Some Key Points on the Impact of Quasispecies in Virology
  • 3.7 Sequence Space and State Transitions
  • 3.7.1 Virus Evolution as a Movement in Sequence Space
  • 3.7.2 Exploration of Sequence Space and the Sampling Problem: Viral Population Size as a Key Parameter
  • 3.8 Modulating Effects of Mutant Spectra: Complementation and Interference: An Ensemble as the Unit of Selection
  • 3.8.1 Molecular Mechanisms of Complementation and Interference
  • 3.8.2 Individual Versus Group Selection
  • 3.8.3 Stochastic Effects in Selected Collectivities
  • 3.9 Viral Populations in Connection with Biological Complexity
  • 3.10 Overview and Concluding Remarks
  • References
  • Chapter 4: Interaction of Virus Populations with Their Hosts
  • 4.1 Contrasting Viral and Host Population Numbers
  • 4.1.1 Productive Power of Some Viral Infections
  • 4.1.2 Population Size Limitations and the Effect of Bottlenecks: The Effective Population Size
  • 4.2 Types of Constraints and Evolutionary Trade-Offs in Virus-Host Interactions
  • 4.2.1 Long-term History Dictates Basal Constraints
  • 4.2.2 Cell-dependent Constraints: No Free Lunch
  • 4.2.3 Constraints in Host Organisms: Contrast with Man-made Antiviral Interventions
  • 4.3 Codon Usage as a Selective Constraint: Virus Attenuation Through Codon and Codon-pair Deoptimization
  • 4.3.1 The Synonymous Codon Space Can Affect an Evolutionary Outcome
  • 4.4 Modifications of Host Cell Tropism and Host Range
  • 4.4.1 Nonstructural Viral Proteins and RNA in Cell Tropism and Host Range of Viruses
  • 4.5 Trait Coevolution: Mutual Influences Between Antigenic Variation and Tropism Change
  • 4.6 Escape from Antibody and Cytotoxic T Cell Responses in Viral Persistence: Fitness Cost
  • 4.7 Antigenic Variation in the Absence of Immune Selection
  • 4.8 Constraints as a Demand on Mutation Rate Levels
  • 4.9 Multifunctional Viral Proteins in Interaction with Host Factors: Joker Substitutions
  • 4.10 Alternating Selective Pressures: The Case of Arboviruses
  • 4.11 Overview and Concluding Remarks
  • References
  • Chapter 5: Viral Fitness as a Measure of Adaptation
  • 5.1 Origin of the Fitness Concept and Its Relevance to Viruses
  • 5.1.1 Measurement of Viral Fitness
  • 5.1.2 Power and Limitations of Fitness Measurements
  • 5.1.3 Dissection of Fitness Determinants
  • 5.2 The Challenge of Fitness In Vivo
  • 5.3 Fitness Landscapes
  • 5.3.1 Justification of Ruggedness in Fitness Landscapes for Viruses
  • 5.4 Population Factors on Fitness Variations: Collective Fitness and Perturbations by Environmental Heterogeneity
  • 5.5 Quasispecies Memory and Fitness Recovery
  • 5.5.1 Implications of Quasispecies Memory: Harbinger Mutations
  • 5.6 The Relationship Between Fitness and Virulence
  • 5.7 Fitness Landscapes for Survival: The Advantage of the Flattest
  • 5.8 Fitness and Function
  • 5.9 Epidemiological Fitness
  • 5.10 Overview and Concluding Remarks
  • References
  • Chapter 6: Virus Population Dynamics Examined with Experimental Model Systems
  • 6.1 Value of Experimental Evolution
  • 6.2 Experimental Systems in Cell Culture and In Vivo
  • 6.2.1 "To Culture is to Disturb"
  • 6.2.2 Experimental Evolution In Vivo
  • 6.3 Viral Dynamics in Controlled Environments: Alterations of Viral Subpopulations
  • 6.4 Persistent Infections in Cell Culture: Virus-cell Coevolution
  • 6.4.1 Back Again 4000 Million Years: Contingency in Evolution
  • 6.5 Teachings from Plaque-to-Plaque Transfers
  • 6.5.1 Muller's Ratchet and the Advantage of Sex
  • 6.5.2 Molecular Basis of Fitness Decrease: Deep Fluctuations, Massive Extinctions, and Rare Survivors
  • 6.6 Limits to Fitness Gain and Loss
  • 6.7 Competitive Exclusion Principle and Red Queen Hypothesis
  • 6.7.1 Contingent Neutrality in Virus
  • 6.8 Studies with Reconstructed Quasispecies
  • 6.9 Quasispecies Dynamics in Cell Culture and In Vivo
  • 6.10 Overview and Concluding Remarks
  • References
  • Chapter 7: Long-term Virus Evolution in Nature
  • 7.1 Introduction to the Spread of Viruses. Outbreaks, Epidemics, and Pandemics
  • 7.2 Reproductive Ratio as a Predictor of Epidemic Potential. Indeterminacies in Transmission Events
  • 7.3 Rates of Virus Evolution in Nature
  • 7.3.1 Influence of the Time of Sampling
  • 7.3.2 Interhost Versus Intrahost Rate of Evolution
  • 7.3.3 Rate Discrepancies and the Clock Hypothesis
  • 7.4 Long-term Antigenic Diversification of Viruses
  • 7.4.1 Widely Different Number of Serotypes Among Genetically Variable Viruses
  • 7.4.2 Similar Frequencies of Monoclonal Antibody-escape Mutants in Viruses Differing in Antigenic Diversity
  • 7.5 Comparing Viral Genomes. Sequence Alignments and Databases
  • 7.6 Phylogenetic Relationships Among Viruses. Evolutionary Models
  • 7.7 Extinction, Survival, and Emergence of Viral Pathogens. Back to the Mutant Clouds
  • 7.7.1 Factors in Viral Emergence
  • 7.7.2 Complexity Revisited
  • 7.8 Overview and Concluding Remarks
  • References
  • Chapter 8: Quasispecies Dynamics in Disease Prevention and Control
  • 8.1 Medical Interventions as Selective Constraints
  • 8.2 Different Manifestations of Virus Evolution in the Prevention and Treatment of Viral Disease
  • 8.3 Antiviral Vaccines and the Adaptive Potential of Viruses
  • 8.3.1 Some Requirements for the Design of Vaccines to Control Highly Variable Viruses
  • 8.3.2 Vaccination-Induced Evolution
  • 8.4 Resistance to Antiviral Inhibitors
  • 8.4.1 Replicative Load and Antiviral Resistance
  • 8.4.2 Barriers to Drug Resistance
  • 8.4.3 Drug Efficacy, Mutant Frequencies, and Selection of Escape Mutants
  • 8.4.4 Phenotypic Barrier and Selective Strength
  • 8.4.5 Multiple Pathways and Evolutionary History in the Acquisition of Drug Resistance
  • 8.5 Molecular Mechanisms of Antiviral Resistance
  • 8.5.1 Some Examples with HIV-1
  • 8.5.2 Mutation Site and Functional Barrier
  • 8.5.3 Additional Considerations on Escape Mutant Frequencies
  • 8.6 Antiviral Resistance Without Prior Exposure to Antiviral Agents
  • 8.7 Fitness or a Fitness-Associated Trait as a Multidrug-Resistance Mechanism
  • 8.8 Viral Load, Fitness, and Disease Progression
  • 8.9 Limitations of Simplified Reagents and Small Molecules as Antiviral Agents
  • 8.10 "Hit Early, Hit Hard"
  • 8.11 Information and Global Action
  • 8.12 Overview and Concluding Remarks
  • References
  • Chapter 9: Trends in Antiviral Strategies
  • 9.1 The Challenge
  • 9.1.1 Virus as Moving Targets
  • 9.2 Practiced and Proposed Strategies to Confront the Moving Target Challenge with Antiviral Inhibitors
  • 9.2.1 Combination Treatments
  • 9.2.2 Split Treatments
  • 9.2.3 Targeting Cellular Functions
  • 9.2.4 Use of Drugs That Stimulate the Host Innate Immune System
  • 9.2.5 Combined Use of Immunotherapy and Chemotherapy
  • 9.3 Lethal Mutagenesis and the Error Threshold
  • 9.3.1 Reconciliation of Theory and Experiment: A Proposal
  • 9.4 Virus Extinction by Mutagenic Agents
  • 9.4.1 The Search for New Mutagenic Nucleotide Analogs
  • 9.5 Lethal Mutagenesis In Vivo: Complications Derived From Multiple Mechanisms of Drug Action-The Case of Ribavirin
  • 9.6 Virus Resistance to Mutagenic Agents: Multiple Mechanisms and Evidence of Abortive Escape Pathways
  • 9.6.1 Unpredictable Effects of Some Polymerase Substitutions
  • 9.6.2 Polymerase Fidelity and Modulation of Nucleotide Incorporation
  • 9.7 Virus Extinction as the Outcome of Replacement of Virus Subpopulations: Tempo and Mode of Mutation Acquisition
  • 9.8 The Interplay Between Inhibitors and Mutagenic Agents in Viral Populations: Sequential Versus Combination Treatments
  • 9.9 Prospects for a Clinical Application of Lethal Mutagenesis
  • 9.10 Some Atypical Proposals
  • 9.11 Overview and Concluding Remarks
  • References
  • Chapter 10: Collective Population Effects in Nonviral Systems
  • 10.1 Concept Generalization
  • 10.2 Viruses and Cells: The Genome Size-Mutation-Time Coordinates Revisited
  • 10.2.1 A Comparison of Antiviral and Antibiotic Resistance
  • 10.3 Darwinian Principles and Intrapopulation Interactions Acting on Cell Populations
  • 10.4 The Dynamics of Unicellular Parasites in the Control of Parasitic Disease
  • 10.5 Cancer Dynamics: Heterogeneity and Group Behavior
  • 10.5.1 The Two-Component Theory of Cancer: Similarities with Other Biological Systems
  • 10.6 Collective Behavior of Prions
  • 10.7 Molecular Mechanisms of Variation and Clonality in Evolution
  • 10.8 Genomes, Clones, Consortia, Networks, and Power Laws
  • 10.9 An Additional Level of Virus Vulnerability?
  • 10.10 Overview and Concluding Remarks
  • References
  • Further Reading
  • Author Index
  • Subject Index
  • Back Cover
Chapter 1

Introduction to Virus Origins and Their Role in Biological Evolution


Abstract


Viruses are extremely abundant and diverse parasites of cells. They might have arisen during an early phase of the evolution of life on Earth dominated by RNA or RNA-like macromolecules, or when a cellular world was already well established. The theories of the origin of life on Earth shed light on the possible origin of primitive viruses or virus-like genetic elements in our biosphere. Some features of present day viruses, notably error-prone replication, might be a consequence of the selective forces that mediated their ancestral origin. Two views on the role of viruses in our biosphere predominate: viruses considered as opportunistic, selfish elements, and viruses considered as active participants in the construction of the cellular world via lateral transfers of genes. These two models bear on considering viruses predominantly as disease agents or predominantly as cooperators in the shaping of differentiated cellular organisms.

Keywords

RNA world, Replicon

Virus origins

Microbial evolution

Biosphere

Lateral gene transfer

Chapter Contents

1.1 Considerations on Biological Diversity   2

1.2 Some Questions of Current Virology and the Scope of This Book   3

1.3 The Staggering Ubiquity and Diversity of Viruses: Limited Morphotypes   4

1.4 Origin of Life: A Brief Historical Account and Current Views   8

1.4.1 Early Synthesis of Oligonucleotides: A Possible Ancestral Positive Selection   10

1.4.2 A Primitive RNA World   11

1.4.3 Life from Mistakes, Information from Noninformation: Origin of Replicons   13

1.4.4 Uptake of Energy and a Second Primitive Positive Selection   15

1.5 Theories of the Origins of Viruses   17

1.5.1 Viruses Are Remnants of Primeval Genetic Elements   18

1.5.2 Viruses Are the Result of Regressive Microbial Evolution   19

1.5.3 Viruses Are Liberated Autonomous Entities   20

1.5.4 Viruses Are Elements for Long-Term Coevolution   20

1.5.5 Viruses from Vesicles   21

1.6 Being Alive Versus Being Part of Life   22

1.7 Role of Viruses in the Evolution of the Biosphere   23

1.7.1 Current Exchanges of Genetic Material   24

1.7.2 Symbiotic Relationships   25

1.8 Virus and Disease   25

1.9 Overview and Concluding Remarks   26

References   27

Abbreviations

AIDS acquired immune deficiency syndrome

APOBEC apolipoprotein B mRNA editing complex

CCMV cowpea chlorotic mottle virus

dsRNA double stranded RNA

E. coli Escherichia coli

eHBVs endogenous hepatitis B viruses

HBV hepatitis B virus

HCV hepatitis C virus

HDV hepatitis delta virus

HIV-1 human immunodeficiency virus type 1

ICTV International Committee on Taxonomy of Viruses

Kbp thousand base pairs

mRNA messenger RNA

PMWS postweaning multisystemic wasting syndrome

RT reverse transcriptase

RdRp RNA-dependent RNA polymerase

ssRNA single stranded RNA

T7 bacteriophage T7

tRNA transfer RNA

UV ultraviolet

1.1 Considerations on Biological Diversity


To approach the behavior of viruses acting as populations, we must first examine the diversity of the present-day biosphere, and the physical and biological context in which primitive viral forms might have arisen. Evolution pervades nature. Thanks to new theories and to the availability of powerful instruments and experimental procedures, which together constitute the very roots of scientific progress, we are aware that the physical and biological worlds are evolving constantly. Several classes of energy have gradually shaped matter and living entities, basically as the outcome of random events and Darwinian natural selection in its broadest sense. The identification of DNA as the genetic material, and the advent of genomics in the second half of the twentieth century unveiled an astonishing degree of diversity within the living world that derives mainly from combinations of four classes of nucleotides. Biodiversity, a term coined by O. Wilson in 1984, is a feature of all living beings, be multicellular differentiated organisms, single cell organisms, or subcellular genetic elements, among them the viruses. Next generation sequencing methods developed at the beginning of the twenty-first century, which allow thousands of sequences from the same biological sample (a microbial community, a tumor, or a viral population) to be determined, has further documented the presence of myriads of variants in a "single biological entity" or in "communities of biological entities." Differences extend to individuals that belong to the same biological group, be it Homo sapiens, Droshophila melanogaster, Escherichia coli, or human immunodeficiency virus type 1 (HIV-1). No exceptions have been described.

During decades, in the first half of the twentieth century, population genetics had as one of its tenets that genetic variation due to mutation had for the most part been originated in a remote past. It was generally thought that the present-day diversity was essentially brought about by the reassortment of chromosomes during sexual reproduction. This view was weakened by the discovery of extensive genetic polymorphisms, first in Drosophila and humans, through indirect analyses of electrophoretic mobility of enzymes, detected by in situ activity assays to yield zymograms that were displayed as electromorphs. These early studies on allozymes were soon extended to other organisms. Assuming that no protein modifications had occurred specifically in some individuals, the results suggested the presence of several different (allelic) forms of a given gene among individuals of the same species, be humans, insects, or bacteria. In the absence of information on DNA nucleotide sequences, the first estimates of heterogeneity from the numbers of electromorphs were collated with the protein sequence information available. An excellent review of these developments (Selander, 1976) ended with the following premonitory sentence on the role of molecular biology in unveiling evolutionarily relevant information: "Considering the magnitude of this effect, we may not be overfanciful to think that future historians will see molecular biology more as the salvation for than, as it first seemed, the nemesis of evolutionary biology."

The conceptual break was confirmed and accentuated when molecular cloning and nucleotide sequencing techniques produced genomic nucleotide sequences from multiple individuals of the same biological species. Variety has shaken our classification schemes, opening a debate on how to define and delimit biological "species" in the microbial world. From a medical perspective it has opened the way to "personalized" medicine, so different are the individual contexts in which disease processes (infectious or other) unfold. Diversity is a general feature of the biological world, with multiple implications for interactions in the environment, and also for human health and disease (Bernstein, 2014).

1.2 Some Questions of Current Virology and the Scope of This Book


Viruses (from the Latin "virus," poison) are no exception regarding diversity. The number of different viruses and their dissimilarity in shape and behavior is astounding. Current estimates indicate that the total number of virus particles in our biosphere reaches 1032, exceeding by one order of magnitude the total number of cells. Viruses are found in surface and deep sea and lake waters, below the Earth surface, in any type of soil, in deserts, and in most environments designated as extreme regarding...

Dateiformat: EPUB
Kopierschutz: Adobe-DRM (Digital Rights Management)

Systemvoraussetzungen:

Computer (Windows; MacOS X; Linux): Installieren Sie bereits vor dem Download die kostenlose Software Adobe Digital Editions (siehe E-Book Hilfe).

Tablet/Smartphone (Android; iOS): Installieren Sie bereits vor dem Download die kostenlose App Adobe Digital Editions (siehe E-Book Hilfe).

E-Book-Reader: Bookeen, Kobo, Pocketbook, Sony, Tolino u.v.a.m. (nicht Kindle)

Das Dateiformat EPUB ist sehr gut für Romane und Sachbücher geeignet - also für "fließenden" Text ohne komplexes Layout. Bei E-Readern oder Smartphones passt sich der Zeilen- und Seitenumbruch automatisch den kleinen Displays an. Mit Adobe-DRM wird hier ein "harter" Kopierschutz verwendet. Wenn die notwendigen Voraussetzungen nicht vorliegen, können Sie das E-Book leider nicht öffnen. Daher müssen Sie bereits vor dem Download Ihre Lese-Hardware vorbereiten.

Weitere Informationen finden Sie in unserer E-Book Hilfe.


Dateiformat: PDF
Kopierschutz: Adobe-DRM (Digital Rights Management)

Systemvoraussetzungen:

Computer (Windows; MacOS X; Linux): Installieren Sie bereits vor dem Download die kostenlose Software Adobe Digital Editions (siehe E-Book Hilfe).

Tablet/Smartphone (Android; iOS): Installieren Sie bereits vor dem Download die kostenlose App Adobe Digital Editions (siehe E-Book Hilfe).

E-Book-Reader: Bookeen, Kobo, Pocketbook, Sony, Tolino u.v.a.m. (nicht Kindle)

Das Dateiformat PDF zeigt auf jeder Hardware eine Buchseite stets identisch an. Daher ist eine PDF auch für ein komplexes Layout geeignet, wie es bei Lehr- und Fachbüchern verwendet wird (Bilder, Tabellen, Spalten, Fußnoten). Bei kleinen Displays von E-Readern oder Smartphones sind PDF leider eher nervig, weil zu viel Scrollen notwendig ist. Mit Adobe-DRM wird hier ein "harter" Kopierschutz verwendet. Wenn die notwendigen Voraussetzungen nicht vorliegen, können Sie das E-Book leider nicht öffnen. Daher müssen Sie bereits vor dem Download Ihre Lese-Hardware vorbereiten.

Weitere Informationen finden Sie in unserer E-Book Hilfe.


Download (sofort verfügbar)

85,62 €
inkl. 19% MwSt.
Download / Einzel-Lizenz
ePUB mit Adobe DRM
siehe Systemvoraussetzungen
PDF mit Adobe DRM
siehe Systemvoraussetzungen
Hinweis: Die Auswahl des von Ihnen gewünschten Dateiformats und des Kopierschutzes erfolgt erst im System des E-Book Anbieters
E-Book bestellen

Unsere Web-Seiten verwenden Cookies. Mit der Nutzung des WebShops erklären Sie sich damit einverstanden. Mehr Informationen finden Sie in unserem Datenschutzhinweis. Ok