scholarly journals Comparative analysis of variation and selection in the HCV genome

2016 ◽  
Author(s):  
Juan Ángel Patiño-Galindo ◽  
Fernando González-Candelas
Keyword(s):  
T Cell ◽  
Secondary Structure ◽  
Positive Selection ◽  
Rna Secondary Structure ◽  
Purifying Selection ◽  
Risk Groups ◽  
Biological Properties ◽  
T Cell Epitopes ◽  
The Impact ◽  
Positively Selected Sites

AbstractGenotype 1 of the hepatitis C virus (HCV) is the most prevalent of the variants of this virus. Its two main subtypes, HCV-1a and HCV-1b, are associated to differences in epidemic features and risk groups, despite sharing similar features in most biological properties. We have analyzed the impact of positive selection on the evolution of these variants using complete genome coding regions, and compared the levels of genetic variability and the distribution of positively selected sites. We have also compared the distributions of positively selected and conserved sites considering different factors such as RNA secondary structure, the presence of different epitopes (antibody, CD4 and CD8), and secondary protein structure. Less than 10% of the genome was found to be under positive selection, and purifying selection was the main evolutionary force in both subtypes. We found differences in the number of positively selected sites between subtypes in several genes (Core, HVR2 inE2, P7, helicase inNS3andNS4a).Heterozygosity values in positively selected sites and the rate of non-synonymous substitutions were significantly higher in subtype HCV-1b. Logistic regression analyses revealed that similar selective forces act at the genome level in both subtypes: RNA secondary structure and CD4 T-cell epitopes are associated with conservation, while CD8 T-cell epitopes are associated with positive selection in both subtypes. These results indicate that similar selective constraints are acting along HCV-1a and HCV-1b genomes, despite some differences in the distribution of positively selected sites at independent genes.

scholarly journals Viral population genomics reveals host and infectivity impact on SARS-CoV-2 adaptive landscape

2021 ◽  
Author(s):  
Kaitlyn Gayvert ◽  
Richard Copin ◽  
Sheldon McKay ◽  
Ian Setliff ◽  
Wei Keat Lim ◽  
...  
Keyword(s):  
T Cell ◽  
Population Genomics ◽  
Cell Epitope ◽  
Purifying Selection ◽  
Spike Protein ◽  
Viral Population ◽  
Adaptive Landscape ◽  
T Cell Epitopes ◽  
Treatment Development ◽  
The Impact

Public health surveillance, drug treatment development, and optimization of immunological interventions all depend on understanding pathogen adaptation, which differ for specific pathogens. SARS-CoV-2 is an exceptionally successful human pathogen, yet complete understanding of the forces driving its evolution is lacking. Here, we leveraged almost four million SARS-CoV-2 sequences originating mostly from non-vaccinated naive patients to investigate the impact of functional constraints and natural immune pressures on the sequence diversity of the SARS-CoV-2 genome. Overall, we showed that the SARS-CoV-2 genome is under strong and intensifying levels of purifying selection with a minority of sites under diversifying pressure. With a particular focus on the spike protein, we showed that sites under selection were critical for protein stability and virus fitness related to increased infectivity and/or reduced neutralization by convalescent sera. We investigated the genetic diversity of SARS-CoV-2 B and T cell epitopes and determined that the currently known T cell epitope sequences were highly conserved. Outside of the spike protein, we observed that mutations under selection in variants of concern can be associated to beneficial outcomes for the virus. Altogether, the results yielded a comprehensive map of all sites under selection across the entirety of SARS-CoV-2 genome, highlighting targets for future studies to better understand the virus spread, evolution and success.

scholarly journals Positive Selection in CD8+T-Cell Epitopes of Influenza Virus Nucleoprotein Revealed by a Comparative Analysis of Human and Swine Viral Lineages

2015 ◽  
Vol 89 (22) ◽  
pp. 11275-11283 ◽  
Author(s):  
Heather M. Machkovech ◽  
Trevor Bedford ◽  
Marc A. Suchard ◽  
Jesse D. Bloom
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Positive Selection ◽  
Swine Influenza ◽  
Selective Advantage ◽  
Influenza Viruses ◽  
T Cell Epitopes ◽  
Human Influenza ◽  
Human Influenza Virus

ABSTRACTNumerous experimental studies have demonstrated that CD8+T cells contribute to immunity against influenza by limiting viral replication. It is therefore surprising that rigorous statistical tests have failed to find evidence of positive selection in the epitopes targeted by CD8+T cells. Here we use a novel computational approach to test for selection in CD8+T-cell epitopes. We define all epitopes in the nucleoprotein (NP) and matrix protein (M1) with experimentally identified human CD8+T-cell responses and then compare the evolution of these epitopes in parallel lineages of human and swine influenza viruses that have been diverging since roughly 1918. We find a significant enrichment of substitutions that alter human CD8+T-cell epitopes in NP of human versus swine influenza virus, consistent with the idea that these epitopes are under positive selection. Furthermore, we show that epitope-altering substitutions in human influenza virus NP are enriched on the trunk versus the branches of the phylogenetic tree, indicating that viruses that acquire these mutations have a selective advantage. However, even in human influenza virus NP, sites in T-cell epitopes evolve more slowly than do nonepitope sites, presumably because these epitopes are under stronger inherent functional constraint. Overall, our work demonstrates that there is clear selection from CD8+T cells in human influenza virus NP and illustrates how comparative analyses of viral lineages from different hosts can identify positive selection that is otherwise obscured by strong functional constraint.IMPORTANCEThere is a strong interest in correlates of anti-influenza immunity that are protective against diverse virus strains. CD8+T cells provide such broad immunity, since they target conserved viral proteins. An important question is whether T-cell immunity is sufficiently strong to drive influenza virus evolution. Although many studies have shown that T cells limit viral replication in animal models and are associated with decreased symptoms in humans, no studies have proven with statistical significance that influenza virus evolves under positive selection to escape T cells. Here we use comparisons of human and swine influenza viruses to rigorously demonstrate that human influenza virus evolves under pressure to fix mutations in the nucleoprotein that promote escape from T cells. We further show that viruses with these mutations have a selective advantage since they are preferentially located on the “trunk” of the phylogenetic tree. Overall, our results show that CD8+T cells targeting nucleoprotein play an important role in shaping influenza virus evolution.

scholarly journals Computational Eurotransplant kidney allocation simulations demonstrate the feasibility and benefit of T-cell epitope matching

2021 ◽  
Vol 17 (7) ◽  
pp. e1009248
Author(s):  
Matthias Niemann ◽  
Nils Lachmann ◽  
Kirsten Geneugelijk ◽  
Eric Spierings
Keyword(s):  
T Cell ◽  
Cell Epitope ◽  
Haplotype Frequency ◽  
Deceased Donor ◽  
Waiting List ◽  
T Cell Epitopes ◽  
Kidney Allocation ◽  
Virtual Population ◽  
Considerable Impact ◽  
The Impact

The EuroTransplant Kidney Allocation System (ETKAS) aims at allocating organs to patients on the waiting list fairly whilst optimizing HLA match grades. ETKAS currently considers the number of HLA-A, -B, -DR mismatches. Evidently, epitope matching is biologically and clinically more relevant. We here executed ETKAS-based computer simulations to evaluate the impact of epitope matching on allocation and compared the strategies. A virtual population of 400,000 individuals was generated using the National Marrow Donor Program (NMDP) haplotype frequency dataset of 2011. Using this population, a waiting list of 10,400 patients was constructed and maintained during simulation, matching the 2015 Eurotransplant Annual Report characteristics. Unacceptable antigens were assigned randomly relative to their frequency using HLAMatchmaker. Over 22,600 kidneys were allocated in 10 years in triplicate using Markov Chain Monte Carlo simulations on 32-CPU-core cloud-computing instances. T-cell epitopes were calculated using the www.pirche.com portal. Waiting list effects were evaluated against ETKAS for five epitope matching scenarios. Baseline simulations of ETKAS slightly overestimated reported average HLA match grades. The best balanced scenario maintained prioritisation of HLA A-B-DR fully matched donors while replacing the HLA match grade by PIRCHE-II score and exchanging the HLA mismatch probability (MMP) by epitope MMP. This setup showed no considerable impact on kidney exchange rates and waiting time. PIRCHE-II scores improved, whereas the average HLA match grade diminishes slightly, yet leading to an improved estimated graft survival. We conclude that epitope-based matching in deceased donor kidney allocation is feasible while maintaining equal balances on the waiting list.

scholarly journals SSS-test: a novel test for detecting positive selection on RNA secondary structure

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Maria Beatriz Walter Costa ◽  
Christian Höner zu Siederdissen ◽  
Marko Dunjić ◽  
Peter F. Stadler ◽  
Katja Nowick
Keyword(s):  
Secondary Structure ◽  
Positive Selection ◽  
Rna Secondary Structure

scholarly journals Immunoinformatic Analysis Reveals Antigenic Heterogeneity of Epstein-Barr Virus Is Immune-Driven

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana Cirac ◽  
Remy Poirey ◽  
Michael Dieckmeyer ◽  
Klaus Witter ◽  
Henri-Jacques Delecluse ◽  
...  
Keyword(s):  
T Cell ◽  
Epstein Barr Virus ◽  
Cd4 T Cell ◽  
Immune Recognition ◽  
T Cell Epitopes ◽  
Barr Virus ◽  
Data Mining Approach ◽  
Epstein Barr ◽  
Relationship Of ◽  
The Impact

Whole genome sequencing of Epstein-Barr virus (EBV) isolates from around the world has uncovered pervasive strain heterogeneity, but the forces driving strain diversification and the impact on immune recognition remained largely unknown. Using a data mining approach, we analyzed more than 300 T-cell epitopes in 168 published EBV strains. Polymorphisms were detected in approximately 65% of all CD8+ and 80% of all CD4+ T-cell epitopes and these numbers further increased when epitope flanking regions were included. Polymorphisms in CD8+ T-cell epitopes often involved MHC anchor residues and resulted in changes of the amino acid subgroup, suggesting that only a limited number of conserved T-cell epitopes may represent generic target antigens against different viral strains. Although considered the prototypic EBV strain, the rather low degree of overlap with most other viral strains implied that B95.8 may not represent the ideal reference strain for T-cell epitopes. Instead, a combinatorial library of consensus epitopes may provide better targets for diagnostic and therapeutic purposes when the infecting strain is unknown. Polymorphisms were significantly enriched in epitope versus non-epitope protein sequences, implicating immune selection in driving strain diversification. Remarkably, CD4+ T-cell epitopes in EBNA2, EBNA-LP, and the EBNA3 family appeared to be under negative selection pressure, hinting towards a beneficial role of immune responses against these latency type III antigens in virus biology. These findings validate this immunoinformatics approach for providing novel insight into immune targets and the intricate relationship of host defense and virus evolution that may also pertain to other pathogens.

scholarly journals Individual HLA-A, -B, -C, and -DRB1 Genotypes Are No Major Factors Which Determine COVID-19 Severity

2021 ◽  
Vol 12 ◽  
Author(s):  
Johannes Schetelig ◽  
Falk Heidenreich ◽  
Henning Baldauf ◽  
Sarah Trost ◽  
Bose Falk ◽  
...  
Keyword(s):  
T Cell ◽  
Peptide Binding ◽  
T Cell Response ◽  
Heterozygote Advantage ◽  
T Cell Epitopes ◽  
Binding Properties ◽  
Cell Responses ◽  
Major Factors ◽  
The Impact ◽  
Hla Molecules

HLA molecules are key restrictive elements to present intracellular antigens at the crossroads of an effective T-cell response against SARS-CoV-2. To determine the impact of the HLA genotype on the severity of SARS-CoV-2 courses, we investigated data from 6,919 infected individuals. HLA-A, -B, and -DRB1 allotypes grouped into HLA supertypes by functional or predicted structural similarities of the peptide-binding grooves did not predict COVID-19 severity. Further, we did not observe a heterozygote advantage or a benefit from HLA diplotypes with more divergent physicochemical peptide-binding properties. Finally, numbers of in silico predicted viral T-cell epitopes did not correlate with the severity of SARS-CoV-2 infections. These findings suggest that the HLA genotype is no major factor determining COVID-19 severity. Moreover, our data suggest that the spike glycoprotein alone may allow for abundant T-cell epitopes to mount robust T-cell responses not limited by the HLA genotype.

scholarly journals Implications of SARS-CoV-2 Mutations for Genomic RNA Structure and Host microRNA Targeting

2020 ◽  
Vol 21 (13) ◽  
pp. 4807 ◽  
Author(s):  
Ali Hosseini Rad SM ◽  
Alexander D. McLellan
Keyword(s):  
Secondary Structure ◽  
Rna Structure ◽  
Rna Secondary Structure ◽  
Vaccine Development ◽  
Viral Fitness ◽  
Host Cells ◽  
Splice Sites ◽  
Genomic Rna ◽  
Zoonotic Pathogen ◽  
The Impact

The SARS-CoV-2 virus is a recently-emerged zoonotic pathogen already well adapted to transmission and replication in humans. Although the mutation rate is limited, recently introduced mutations in SARS-CoV-2 have the potential to alter viral fitness. In addition to amino acid changes, mutations could affect RNA secondary structure critical to viral life cycle, or interfere with sequences targeted by host miRNAs. We have analysed subsets of genomes from SARS-CoV-2 isolates from around the globe and show that several mutations introduce changes in Watson–Crick pairing, with resultant changes in predicted secondary structure. Filtering to targets matching miRNAs expressed in SARS-CoV-2-permissive host cells, we identified ten separate target sequences in the SARS-CoV-2 genome; three of these targets have been lost through conserved mutations. A genomic site targeted by the highly abundant miR-197-5p, overexpressed in patients with cardiovascular disease, is lost by a conserved mutation. Our results are compatible with a model that SARS-CoV-2 replication within the human host is constrained by host miRNA defences. The impact of these and further mutations on secondary structures, miRNA targets or potential splice sites offers a new context in which to view future SARS-CoV-2 evolution, and a potential platform for engineering conditional attenuation to vaccine development, as well as providing a better understanding of viral tropism and pathogenesis.

scholarly journals Mutation of the phospholipase C-γ1–binding site of LAT affects both positive and negative thymocyte selection

2005 ◽  
Vol 201 (7) ◽  
pp. 1125-1134 ◽  
Author(s):  
Connie L. Sommers ◽  
Jan Lee ◽  
Kevin L. Steiner ◽  
Jordan M. Gurson ◽  
Corinne L. DePersis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
Phospholipase C ◽  
Negative Selection ◽  
T Cell Development ◽  
Adaptor Protein ◽  
Cell Development ◽  
Autoreactive T Cells ◽  
The Impact

Linker for activation of T cells (LAT) is a scaffolding adaptor protein that is critical for T cell development and function. A mutation of LAT (Y136F) that disrupts phospholipase C-γ1 activation and subsequent calcium influx causes a partial block in T cell development and leads to a severe lymphoproliferative disease in homozygous knock-in mice. One possible contribution to the fatal disease of LAT Y136F knock-in mice could be from autoreactive T cells generated in these mice because of altered thymocyte selection. To examine the impact of the LAT Y136F mutation on thymocyte positive and negative selection, we bred this mutation onto the HY T cell receptor (TCR) transgenic, recombination activating gene-2 knockout background. Female mice with this genotype showed a severe defect in positive selection, whereas male mice exhibited a phenotype resembling positive selection (i.e., development and survival of CD8hi HY TCR-specific T cells) instead of negative selection. These results support the hypothesis that in non-TCR transgenic, LAT Y136F knock-in mice, altered thymocyte selection leads to the survival and proliferation of autoreactive T cells that would otherwise be negatively selected in the thymus.

scholarly journals The Mechanism of Action of Antigen Processing Independent T Cell Epitopes Designed for Immunotherapy of Autoimmune Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Ella R. Shepard ◽  
Anja Wegner ◽  
Elaine V. Hill ◽  
Bronwen R. Burton ◽  
Sarah Aerts ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Antigen Processing ◽  
Repeated Administration ◽  
T Cell Epitopes ◽  
Regulatory Cells ◽  
T Cell Signaling ◽  
The Impact

Immunotherapy with antigen-processing independent T cell epitopes (apitopes) targeting autoreactive CD4+ T cells has translated to the clinic and been shown to modulate progression of both Graves’ disease and multiple sclerosis. The model apitope (Ac1-9[4Y]) renders antigen-specific T cells anergic while repeated administration induces both Tr1 and Foxp3+ regulatory cells. Here we address why CD4+ T cell epitopes should be designed as apitopes to induce tolerance and define the antigen presenting cells that they target in vivo. Furthermore, we reveal the impact of treatment with apitopes on CD4+ T cell signaling, the generation of IL-10-secreting regulatory cells and the systemic migration of these cells. Taken together these findings reveal how apitopes induce tolerance and thereby mediate antigen-specific immunotherapy of autoimmune diseases.

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