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Daniel Dhumeaux - One of the best experts on this subject based on the ideXlab platform.
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hepatitis c virus Quasispecies variability modulates nonstructural protein 5a transcriptional activation pointing to cellular compartmentalization of virus host interactions
Journal of Virology, 2004Co-Authors: Muriel Pellerin, Francois Penin, Yolanda Lopezaguirre, Daniel Dhumeaux, Jeanmichel PawlotskyAbstract:Hepatitis C virus (HCV) behaves in infected patients as a complex mixture of genetically distinct but closely related variants referred to as a “Quasispecies.” By using Quasispecies analysis strategies, we showed that HCV nonstructural protein 5A (NS5A) has a Quasispecies distribution in infected humans and that NS5A Quasispecies undergo significant genetic evolution over time, as a result of random accumulation of nucleotide mutations during replication. Genetic evolution of the NS5A Quasispecies results in sporadic amino acid changes in the protein sequence. By using the functional in vitro model of HCV NS5A transcriptional activation in Saccharomyces cerevisiae, we showed that natural NS5A Quasispecies variants induce different levels of transcriptional activation, according to the charge of the residues (and possibly minor conformational changes) in the Quasispecies variant sequence. These findings show that the accumulation of mutations on HCV genomes during replication randomly generates variant proteins with quantitatively different functional properties. The fact that each new variant protein is initially produced in a single infected hepatocyte and may or may not subsequently spread throughout the liver (depending on the replication capacities of the variant virus) points to cellular compartmentalization of virus-host interactions during chronic infection. This feature of Quasispecies-distributed viruses could play an important role in various aspects of the viral life cycle and related disease.
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evolution of the hepatitis c virus second envelope protein hypervariable region in chronically infected patients receiving alpha interferon therapy
Journal of Virology, 1999Co-Authors: Jeanmichel Pawlotsky, Muriel Pellerin, Daniel Dhumeaux, Georgios Germanidis, Pierreolivier Frainais, Magali Bouvier, Alexandre SoulierAbstract:Sustained hepatitis C virus (HCV) RNA clearance is achieved in 8 to 12% of patients with chronic HCV infection treated with alpha interferon (IFN-α) at the approved dose of 3 MU three times a week for 6 months and in about 25% of those receiving this treatment for 12 months. We used single-strand conformation polymorphism analysis combined with cloning and sequencing strategies to characterize the genetic evolution of HCV second envelope gene hypervariable region 1 (HVR1) Quasispecies during and after IFN therapy in patients who failed to clear HCV RNA. Sustained HCV RNA clearance was achieved in 6% of patients. Profound changes in HVR1 Quasispecies major variants were estimated to occur in 70% of the patients during and after therapy. These changes were evolutionary and were characterized by shifts in the virus population, related to selection and subsequent diversification of minor pretreatment variants. The Quasispecies changes appeared to be induced by changes in the host environment likely resulting from the IFN-induced enhancement and post-IFN attenuation of neutralizing and possibly cytotoxic responses against HVR1. The remaining patients had no apparent changes in HVR1 Quasispecies major variants, suggesting selection of major pretreatment variants, but some changes were observed in other genomic regions. We conclude that IFN-α administration and withdrawal profoundly alters the nature of circulating HCV Quasispecies, owing to profound changes in virus-host interactions, in patients in whom sustained HCV RNA clearance fails to occur. These changes are associated with profound alterations of the natural outcome of HCV-related liver disease, raising the hypothesis of a causal relationship.
Sergio R Souza - One of the best experts on this subject based on the ideXlab platform.
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Quasispecies dynamics on a network of interacting genotypes and idiotypes applications to autoimmunity and immunodeficiency
Journal of Statistical Mechanics: Theory and Experiment, 2016Co-Authors: Valmir C Barbosa, R Donangelo, Sergio R SouzaAbstract:In spite of their many facets, the phenomena of autoimmunity and immunodeficiency seem to be related to each other through the subtle links connecting the mutation and action of retroviruses (viruses whose genetic material can find its way into that of the host's cells and destroy them) to immune response and adaptation. In a previous work, we introduced a network model of how a set of interrelated genotypes (called a Quasispecies, in the stationary state, representing for example a population of viruses) and a set of interrelated idiotypes (an idiotypic network, representing the immune system through its population of B and T cells) interact. That model, which does not cover the case of a retroviral Quasispecies, is here extended by the addition of a further parameter (ν) to account for the action of retroviruses (i.e. the destruction of idiotypes by genotypes). We give simulation results within a suitable parameter niche, highlighting the issues of Quasispecies survival and of the onset of autoimmunity through the appearance of the so-called pathogenic idiotypes (those that mimic some external pathogen). Our main findings refer to how ν and λ, a parameter describing the rate at which idiotypes get stimulated, relate to each other. While for the Quasispecies survives at the expense of weakening the immune system significantly or even destroying it, for the fittest genotypes of the Quasispecies become mimicked inside the immune system as pathogenic idiotypes. The latter is in agreement with the current understanding of the HIV Quasispecies.
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Quasispecies dynamics on a network of interacting genotypes and idiotypes applications to autoimmunity and immunodeficiency
arXiv: Populations and Evolution, 2015Co-Authors: Valmir C Barbosa, R Donangelo, Sergio R SouzaAbstract:In spite of their many facets, the phenomena of autoimmunity and immunodeficiency seem to be related to each other through the subtle links connecting retroviral mutation and action to immune response and adaptation. In a previous work, we introduced a network model of how a set of interrelated genotypes (called a Quasispecies, in the stationary state) and a set of interrelated idiotypes (an idiotypic network) interact. That model, which does not cover the case of a retroviral Quasispecies, was instrumental for the study of Quasispecies survival when confronting the immune system and led to the conclusion that, unlike what happens when a Quasispecies is left to evolve by itself, letting genotypes mutate too infrequently leads to the destruction of the Quasispecies. Here we extend that genotype-idiotype interaction model by the addition of a further parameter ($\nu$) to account for the action of retroviruses (i.e., the destruction of idiotypes by genotypes). We give simulation results within a suitable parameter niche, highlighting the issues of Quasispecies survival and of the onset of autoimmunity through the appearance of the so-called pathogenic idiotypes. Our main findings refer to how $\nu$ and $\lambda$, a parameter describing the rate at which idiotypes get stimulated, relate to each other. While for $\nu>\lambda$ the Quasispecies survives at the expense of weakening the immune system significantly or even destroying it, for $\nu<\lambda$ the fittest genotypes of the Quasispecies become mimicked inside the immune system as pathogenic idiotypes. The latter is in agreement with the current understanding of the HIV Quasispecies.
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Quasispecies dynamics on a network of interacting genotypes and idiotypes formulation of the model
Journal of Statistical Mechanics: Theory and Experiment, 2015Co-Authors: Valmir C Barbosa, R Donangelo, Sergio R SouzaAbstract:A Quasispecies is the stationary state of a set of interrelated genotypes that evolve according to the usual principles of selection and mutation. Quasispecies studies have for the most part concentrated on the possibility of errors during genotype replication and their role in promoting either the survival or the demise of the Quasispecies. In a previous work, we introduced a network model of Quasispecies dynamics, based on a single probability parameter (p) and capable of addressing several plausibility issues of previous models. Here we extend that model by pairing its network with another one aimed at modeling the dynamics of the immune system when confronted with the Quasispecies. The new network is based on the idiotypic-network model of immunity and, together with the previous one, constitutes a network model of interacting genotypes and idiotypes. The resulting model requires further parameters and as a consequence leads to a vast phase space. We have focused on a particular niche in which it is possible to observe the trade-offs involved in the Quasispecies' survival or destruction. Within this niche, we give simulation results that highlight some key preconditions for Quasispecies survival. These include a minimum initial abundance of genotypes relative to that of the idiotypes and a minimum value of p. The latter, in particular, is to be contrasted with the stand-alone Quasispecies network of our previous work, in which arbitrarily low values of p constitute a guarantee of Quasispecies survival.
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Quasispecies dynamics on a network of interacting genotypes and idiotypes formulation of the model
arXiv: Populations and Evolution, 2013Co-Authors: Valmir C Barbosa, R Donangelo, Sergio R SouzaAbstract:A Quasispecies is the stationary state of a set of interrelated genotypes that evolve according to the usual principles of selection and mutation. Quasispecies studies have invariably concentrated on the possibility of errors during genotype replication and their role in promoting either the survival or the demise of the Quasispecies. In a previous work [V. C. Barbosa, R. Donangelo, and S. R. Souza, J. Theor. Biol. 312, 114 (2012)], we introduced a network model of Quasispecies dynamics, based on a single probability parameter ($p$) and capable of addressing several plausibility issues of previous models. Here we extend that model by pairing its network with another one aimed at modeling the dynamics of the immune system when confronted with the Quasispecies. The new network is based on the idiotypic-network model of immunity and, together with the previous one, constitutes a network model of interacting genotypes and idiotypes. The resulting model requires further parameters and as a consequence leads to a vast phase space. We have focused on a particular niche in which it is possible to observe the trade-offs involved in the Quasispecies' survival or destruction. Within this niche, we give simulation results that highlight some key preconditions for Quasispecies survival. These include a minimum initial abundance of genotypes relative to that of the idiotypes and a minimum value of $p$. The latter, in particular, is to be contrasted with the stand-alone Quasispecies network of our previous work, in which arbitrarily low values of $p$ constitute a guarantee of Quasispecies survival.
Eric Delwart - One of the best experts on this subject based on the ideXlab platform.
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Population Genetic Analysis of the Protease Locus of Human Immunodeficiency Virus Type 1 Quasispecies Undergoing Drug Selection, Using a Denaturing Gradient-Heteroduplex Tracking Assay
Journal of virology, 2001Co-Authors: Laurence Doukhan, Eric DelwartAbstract:Monitoring the evolution of human immunodeficiency virus type 1 (HIV-1) drug resistance requires measuring the frequency of closely related genetic variants making up the complex viral Quasispecies found in vivo. In order to resolve both major and minor (≥2%) protease gene variants differing by one or more nucleotide substitutions, we analyzed PCR products derived from plasma viral Quasispecies by using a combination of denaturing gradient gel electrophoresis and DNA heteroduplex tracking assays. Correct population sampling of the high level of genetic diversity present within viral Quasispecies could be documented by parallel analysis of duplicate, independently generated PCR products. The composition of genetically complex protease gene Quasispecies remained constant over short periods of time in the absence of treatment and while plasma viremia fell >100-fold following the initiation of protease inhibitor ritonavir monotherapy. Within a month of initiating therapy, a strong reduction in the genetic diversity of plasma viral populations at the selected protease locus was associated with rising plasma viremia and the emergence of drug resistance. The high levels of protease genetic diversity seen before treatment reemerged only months later. In one patient, reduction in genetic diversity at the protease gene was observed concomitantly with an increase in diversity at the envelope gene (E. L. Delwart, P. Heng, A. Neumann, and M. Markowitz, J. Virol. 72:2416-2421, 1998), indicating that opposite population genetic changes can take place in different HIV-1 loci. The rapid emergence of drug-resistant HIV-1 was therefore associated with a strong, although only transient, reduction in genetic diversity at the selected locus. The denaturing gradient-heteroduplex tracking assay is a simple method for the separation and quantitation of very closely related, low-frequency, genetic variants within complex viral populations.
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human immunodeficiency virus type 1 evolution in vivo tracked by dna heteroduplex mobility assays
Journal of Virology, 1994Co-Authors: Eric Delwart, Haynes W Sheppard, Bruce D Walker, Jaap Goudsmit, James I MullinsAbstract:High mutation rates and strong selective pressures imposed on human immunodeficiency viruses in vivo result in the formation of pools of genetic variants known as Quasispecies. DNA heteroduplex mobility and tracking analyses were used to monitor the generation of HIV sequence diversity, to estimate Quasispecies complexity, and to assess the turnover of genetic variants to approach an understanding of the relationship between viral Quasispecies evolution in vivo and disease progression. Proviral DNA pools were nearly homogeneous soon after sexual transmission. The emergence and clearance of individual variants then occurred at different rates in different individuals. High Quasispecies complexity was found in long-term-infected, asymptomatic individuals, while rapid CD4+ cell decline and AIDS were often, but not always, associated with lower Quasispecies complexity. Proviral genetic variation was often low following in vitro culture, because of the outgrowth of one or a few variants that often became more abundant only later as proviruses in peripheral blood mononuclear cells. These studies provide insight into the dynamics of human immunodeficiency virus sequence changes in vivo and illustrate the utility of heteroduplex analysis for the study of phenomena associated with rapid genetic changes.
Raul Andino - One of the best experts on this subject based on the ideXlab platform.
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Quasispecies theory and the behavior of rna viruses
PLOS Pathogens, 2010Co-Authors: Adam S Lauring, Raul AndinoAbstract:A large number of medically important viruses, including HIV, hepatitis C virus, and influenza, have RNA genomes. These viruses replicate with extremely high mutation rates and exhibit significant genetic diversity. This diversity allows a viral population to rapidly adapt to dynamic environments and evolve resistance to vaccines and antiviral drugs. For the last 30 years, Quasispecies theory has provided a population-based framework for understanding RNA viral evolution. A Quasispecies is a cloud of diverse variants that are genetically linked through mutation, interact cooperatively on a functional level, and collectively contribute to the characteristics of the population. Many predictions of Quasispecies theory run counter to traditional views of microbial behavior and evolution and have profound implications for our understanding of viral disease. Here, we discuss basic principles of Quasispecies theory and describe its relevance for our understanding of viral fitness, virulence, and antiviral therapeutic strategy.
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Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population
Nature, 2006Co-Authors: Marco Vignuzzi, Jamie J Arnold, Jeffrey K. Stone, Craig E Cameron, Raul AndinoAbstract:The replication of RNA viruses is associated with a higher mutation rate than is seen in organisms using DNA as their genetic material. This can produce nonviable individuals but also, it has been suggested, some useful variation that could enhance the fitness of virus populations by allowing them to adapt to changing environments encountered during infection. Until now there has been no experimental support for this suggestion, known as the ‘Quasispecies’ hypothesis. But now a search for viruses that copy their genome too accurately has provided support for this idea. Poliovirus isolates carrying a ‘super accurate’ RNA polymerase are less varied and less infectious than normal viruses. These results could have implications for the development of antiviral drugs. An RNA virus population does not consist of a single genotype; rather, it is an ensemble of related sequences, termed Quasispecies1,2,3,4. Quasispecies arise from rapid genomic evolution powered by the high mutation rate of RNA viral replication5,6,7,8. Although a high mutation rate is dangerous for a virus because it results in nonviable individuals, it has been hypothesized that high mutation rates create a ‘cloud’ of potentially beneficial mutations at the population level, which afford the viral Quasispecies a greater probability to evolve and adapt to new environments and challenges during infection4,9,10,11. Mathematical models predict that viral Quasispecies are not simply a collection of diverse mutants but a group of interactive variants, which together contribute to the characteristics of the population4,12. According to this view, viral populations, rather than individual variants, are the target of evolutionary selection4,12. Here we test this hypothesis by examining the consequences of limiting genomic diversity on viral populations. We find that poliovirus carrying a high-fidelity polymerase replicates at wild-type levels but generates less genomic diversity and is unable to adapt to adverse growth conditions. In infected animals, the reduced viral diversity leads to loss of neurotropism and an attenuated pathogenic phenotype. Notably, using chemical mutagenesis to expand Quasispecies diversity of the high-fidelity virus before infection restores neurotropism and pathogenesis. Analysis of viruses isolated from brain provides direct evidence for complementation between members in the Quasispecies, indicating that selection indeed occurs at the population level rather than on individual variants. Our study provides direct evidence for a fundamental prediction of the Quasispecies theory and establishes a link between mutation rate, population dynamics and pathogenesis.
Jeanmichel Pawlotsky - One of the best experts on this subject based on the ideXlab platform.
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hepatitis c virus Quasispecies variability modulates nonstructural protein 5a transcriptional activation pointing to cellular compartmentalization of virus host interactions
Journal of Virology, 2004Co-Authors: Muriel Pellerin, Francois Penin, Yolanda Lopezaguirre, Daniel Dhumeaux, Jeanmichel PawlotskyAbstract:Hepatitis C virus (HCV) behaves in infected patients as a complex mixture of genetically distinct but closely related variants referred to as a “Quasispecies.” By using Quasispecies analysis strategies, we showed that HCV nonstructural protein 5A (NS5A) has a Quasispecies distribution in infected humans and that NS5A Quasispecies undergo significant genetic evolution over time, as a result of random accumulation of nucleotide mutations during replication. Genetic evolution of the NS5A Quasispecies results in sporadic amino acid changes in the protein sequence. By using the functional in vitro model of HCV NS5A transcriptional activation in Saccharomyces cerevisiae, we showed that natural NS5A Quasispecies variants induce different levels of transcriptional activation, according to the charge of the residues (and possibly minor conformational changes) in the Quasispecies variant sequence. These findings show that the accumulation of mutations on HCV genomes during replication randomly generates variant proteins with quantitatively different functional properties. The fact that each new variant protein is initially produced in a single infected hepatocyte and may or may not subsequently spread throughout the liver (depending on the replication capacities of the variant virus) points to cellular compartmentalization of virus-host interactions during chronic infection. This feature of Quasispecies-distributed viruses could play an important role in various aspects of the viral life cycle and related disease.
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evolution of the hepatitis c virus second envelope protein hypervariable region in chronically infected patients receiving alpha interferon therapy
Journal of Virology, 1999Co-Authors: Jeanmichel Pawlotsky, Muriel Pellerin, Daniel Dhumeaux, Georgios Germanidis, Pierreolivier Frainais, Magali Bouvier, Alexandre SoulierAbstract:Sustained hepatitis C virus (HCV) RNA clearance is achieved in 8 to 12% of patients with chronic HCV infection treated with alpha interferon (IFN-α) at the approved dose of 3 MU three times a week for 6 months and in about 25% of those receiving this treatment for 12 months. We used single-strand conformation polymorphism analysis combined with cloning and sequencing strategies to characterize the genetic evolution of HCV second envelope gene hypervariable region 1 (HVR1) Quasispecies during and after IFN therapy in patients who failed to clear HCV RNA. Sustained HCV RNA clearance was achieved in 6% of patients. Profound changes in HVR1 Quasispecies major variants were estimated to occur in 70% of the patients during and after therapy. These changes were evolutionary and were characterized by shifts in the virus population, related to selection and subsequent diversification of minor pretreatment variants. The Quasispecies changes appeared to be induced by changes in the host environment likely resulting from the IFN-induced enhancement and post-IFN attenuation of neutralizing and possibly cytotoxic responses against HVR1. The remaining patients had no apparent changes in HVR1 Quasispecies major variants, suggesting selection of major pretreatment variants, but some changes were observed in other genomic regions. We conclude that IFN-α administration and withdrawal profoundly alters the nature of circulating HCV Quasispecies, owing to profound changes in virus-host interactions, in patients in whom sustained HCV RNA clearance fails to occur. These changes are associated with profound alterations of the natural outcome of HCV-related liver disease, raising the hypothesis of a causal relationship.
