scholarly journals Structural topology defines protective CD8+ T cell epitopes in the HIV proteome

Science ◽  
2019 ◽  
Vol 364 (6439) ◽  
pp. 480-484 ◽  
Author(s):  
Gaurav D. Gaiha ◽  
Elizabeth J. Rossin ◽  
Jonathan Urbach ◽  
Christian Landeros ◽  
David R. Collins ◽  
...  
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Hiv Vaccine ◽  
Amino Acid Residues ◽  
T Cell Epitopes ◽  
Structural Topology ◽  
Leukocyte Antigen ◽  
Immunogen Design ◽  
Mechanistic Basis ◽  
Protein Structure Data

Mutationally constrained epitopes of variable pathogens represent promising targets for vaccine design but are not reliably identified by sequence conservation. In this study, we employed structure-based network analysis, which applies network theory to HIV protein structure data to quantitate the topological importance of individual amino acid residues. Mutation of residues at important network positions disproportionately impaired viral replication and occurred with high frequency in epitopes presented by protective human leukocyte antigen (HLA) class I alleles. Moreover, CD8+ T cell targeting of highly networked epitopes distinguished individuals who naturally control HIV, even in the absence of protective HLA alleles. This approach thereby provides a mechanistic basis for immune control and a means to identify CD8+ T cell epitopes of topological importance for rational immunogen design, including a T cell–based HIV vaccine.

scholarly journals Machine Learning-Enhanced T Cell Neoepitope Discovery for Immunotherapy Design

2019 ◽  
Vol 18 ◽  
pp. 117693511985208 ◽  
Author(s):  
Joana Martins ◽  
Carlos Magalhães ◽  
Miguel Rocha ◽  
Nuno S Osório
Keyword(s):  
Machine Learning ◽  
T Cell ◽  
Human Leukocyte ◽  
Quality Analysis ◽  
T Cell Epitopes ◽  
Fully Integrated ◽  
Leukocyte Antigen ◽  
Cell Responses ◽  
Peptide Interaction ◽  
Peptide Binding Affinity

Immune responses mediated by T cells are aimed at specific peptides, designated T cell epitopes, that are recognized when bound to human leukocyte antigen (HLA) molecules. The HLA genes are remarkably polymorphic in the human population allowing a broad and fine-tuned capacity to bind a wide array of peptide sequences. Polymorphisms might generate neoepitopes by impacting the HLA-peptide interaction and potentially alter the level and type of generated T cell responses. Multiple algorithms and tools based on machine learning (ML) have been implemented and are able to predict HLA-peptide binding affinity with considerable accuracy. Challenges in this field include the availability of adequate epitope datasets for training and benchmarking and the development of fully integrated pipelines going from next-generation sequencing to neoepitope prediction and quality analysis metrics. Effectively predicting neoepitopes from in silico data is a demanding task that has been facilitated by ML and will be of great value for the future of personalized immunotherapies against cancer and other diseases.

The minor histocompatibility antigen HA-3 arises from differential proteasome–mediated cleavage of the lymphoid blast crisis (Lbc) oncoprotein

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 621-629 ◽  
Author(s):  
Eric Spierings ◽  
Anthony G. Brickner ◽  
Jennifer A. Caldwell ◽  
Suzanne Zegveld ◽  
Nia Tatsis ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Processing ◽  
Blast Crisis ◽  
Human Leukocyte ◽  
Target Cells ◽  
T Cell Epitopes ◽  
Minimal Impact ◽  
Leukocyte Antigen ◽  
Genotypic Analysis ◽  
First Time

AbstractMinor histocompatibility (H) antigens crucially affect the outcome of human leukocyte antigen (HLA)–identical allogeneic stem cell transplantation (SCT). To understand the basis of alloimmune responses against minor H antigens, identification of minor H peptides and their antigenicity-determining mechanisms is essential. Here we report the identification of HA-3 and its encoding gene. The HA-3 peptide, VTEPGTAQY (HA-3T), is encoded by the lymphoid blast crisis (Lbc) oncogene. We thus show for the first time that a leukemia-associated oncogene can give rise to immunogenic T-cell epitopes that may have participated in antihost and antileukemic alloimmune responses. Genotypic analysis of HA-3- individuals revealed the allelic counterpart VMEPGTAQY (HA-3M). Despite the lack of T-cell recognition of HA-3- cells, the Thr→Met substitution had only a modest effect on peptide binding to HLA-A1 and a minimal impact on recognition by T cells when added exogenously to target cells. This substitution did not influence transporter associated with antigen processing (TAP) transport, but, in contrast to the HA-3T peptide, HA-3M is destroyed by proteasome-mediated digestion. Thus, the immunogenicity of minor H antigens can result from proteasome-mediated destruction of the negative allelic peptide.

scholarly journals Designing Peptide-Based HIV Vaccine for Chinese

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Jiayi Shu ◽  
Xiaojuan Fan ◽  
Jie Ping ◽  
Xia Jin ◽  
Pei Hao
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Hiv Vaccine ◽  
Cd4 T Cell ◽  
Cell Vaccine ◽  
Vaccine Research ◽  
Leukocyte Antigen ◽  
Cell Responses ◽  
T Cell Vaccine ◽  
Hla Dr

CD4+ T cells are central to the induction and maintenance of CD8+ T cell and antibody-producing B cell responses, and the latter are essential for the protection against disease in subjects with HIV infection. How to elicit HIV-specific CD4+ T cell responses in a given population using vaccines is one of the major areas of current HIV vaccine research. To design vaccine that targets specifically Chinese, we assembled a database that is comprised of sequences from 821 Chinese HIV isolates and 46 human leukocyte antigen (HLA) DR alleles identified in Chinese population. We then predicted 20 potential HIV epitopes using bioinformatics approaches. The combination of these 20 epitopes has a theoretical coverage of 98.1% of the population for both the prevalent HIV genotypes and also Chinese HLA-DR types. We suggest that testing this vaccine experimentally will facilitate the development of a CD4+ T cell vaccine especially catered for Chinese.

scholarly journals Multi-epitope vaccine design using an immunoinformatics approach for 2019 novel coronavirus (SARS-CoV-2)

2020 ◽  
Author(s):  
Ye Feng ◽  
Min Qiu ◽  
Liang Liu ◽  
Shengmei Zou ◽  
Yun Li ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Peptide Vaccine ◽  
Human Leukocyte ◽  
T Cell Epitopes ◽  
Epitope Peptide ◽  
Leukocyte Antigen ◽  
Cellular Immune Responses ◽  
Rapid Dissemination ◽  
Cellular Immune

AbstractA new coronavirus SARS-CoV-2 has caused over 9.2 million infection cases and 475758 deaths worldwide. Due to the rapid dissemination and the unavailability of specific therapy, there is a desperate need for vaccines to combat the epidemic of SARS-CoV-2. An in silico approach based on the available virus genome was applied to identify 19 high immunogenic B-cell epitopes and 499 human-leukocyte-antigen (HLA) restricted T-cell epitopes. Thirty multi-epitope peptide vaccines were designed by iNeo Suite, and manufactured by solid-phase synthesis. Docking analysis showed stable hydrogen bonds of epitopes with their corresponding HLA alleles. When four vaccine peptide candidates from the spike protein of SARS-CoV-2 were selected to immunize mice, a significantly larger amount of IgG in serum as well as an increase of CD19+ cells in ILNs was observed in peptide-immunized mice compared to the control mice. The ratio of IFN-γ-secreting lymphocytes in CD4+ or CD8+ cells in the peptides-immunized mice were higher than that in the control mice. There were also a larger number of IFN-γ-secreting T cells in spleen in the peptides-immunized mice. This study screened antigenic B-cell and T-cell epitopes in all encoded proteins of SARS-CoV-2, and further designed multi-epitope based peptide vaccine against viral structural proteins. The obtained vaccine peptides successfully elicited specific humoral and cellular immune responses in mice. Primate experiments and clinical trial are urgently required to validate the efficacy and safety of these vaccine peptides.ImportanceSo far, a new coronavirus SARS-CoV-2 has caused over 9.2 million infection cases and 475758 deaths worldwide. Due to the rapid dissemination and the unavailability of specific therapy, there is a desperate need for vaccines to combat the epidemic of SARS-CoV-2. Different from the development approaches for traditional vaccines, the development of our peptide vaccine is faster and simpler. In this study, we performed an in silico approach to identify the antigenic B-cell epitopes and human-leukocyte-antigen (HLA) restricted T-cell epitopes, and designed a panel of multi-epitope peptide vaccines. The resulting SARS-CoV-2 multi-epitope peptide vaccine could elicit specific humoral and cellular immune responses in mice efficiently, displaying its great potential in our fight of COVID-19.

scholarly journals Epitope-based peptide vaccine design and target site characterization against novel coronavirus disease caused by SARS-CoV-2

2020 ◽  
Author(s):  
Lin Li ◽  
Ting Sun ◽  
Yufei He ◽  
Wendong Li ◽  
Yubo Fan ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
Vaccine Development ◽  
Peptide Vaccine ◽  
Human Leukocyte ◽  
Surface Glycoprotein ◽  
T Cell Epitopes ◽  
Leukocyte Antigen ◽  
The Stability ◽  
Novel Coronavirus

AbstractThe outbreak of the 2019 novel coronavirus (SARS-CoV-2) has infected thousands of people with a large number of deaths across 26 countries. The sudden appearance of the virus leads to the limited existing therapies for SARS-CoV-2. Therefore, vaccines and antiviral medicines are in desperate need. This study took immune-informatics approaches to identify B- and T-cell epitopes for surface glycoprotein (S) of SARS-CoV-2, followed by estimating their antigenicity and interactions with the human leukocyte antigen (HLA) alleles. We identified four B cell epitopes, two MHC class-I and nine MHC class-II binding T-cell epitopes, which showed highly antigenic features. Allergenicity, toxicity and physiochemical properties analysis confirmed the specificity and selectivity of epitopes. The stability and safety of epitopes were confirmed by digestion analysis. No mutations were observed in all the selected B- and T-cell epitopes across all isolates from different locations worldwide. Epitopes were thus identified and some of them can be potential candidates for vaccine development.

scholarly journals T-Cell Epitopes and Human Leukocyte Antigen Restriction Elements of an Immunodominant Antigen of Blastomyces dermatitidis

2000 ◽  
Vol 68 (2) ◽  
pp. 502-510 ◽  
Author(s):  
W. L. Chang ◽  
R. G. Audet ◽  
B. D. Aizenstein ◽  
L. H. Hogan ◽  
R. I. DeMars ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tandem Repeat ◽  
Human Leukocyte ◽  
Blastomyces Dermatitidis ◽  
T Cell Epitopes ◽  
Leukocyte Antigen ◽  
Immunodominant Antigen ◽  
N Terminus

ABSTRACT Humans infected with the dimorphic fungus Blastomyces dermatitidis develop strong T-lymphocyte responses to WI-1, an immunodominant antigen that has been shown to elicit protective immunity in mice. In the present study, the T-cell epitopes of WI-1 and human leukocyte antigen (HLA) restricting elements that display them were investigated. Peripheral blood mononuclear cells (PBMC) from 37 patients with a confirmed history of blastomycosis were tested for a response to WI-1 in primary proliferation assays; PBMC from 35 (95%) responded. Six patients whose PBMC proliferated strongly in response to WI-1 (defined as a stimulation index greater than 50) were tested further for responses to subcloned, recombinant fragments of the antigen. These patients responded chiefly to sequences within the N terminus and the 25-amino-acid tandem repeat. Cloned CD4+ T cells from an infected individual were used to delineate more precisely the peptide epitopes in the fragments and HLA restricting elements that present them. A majority of the T-cell clones recognized an epitope spanning amino acids 149 to 172 within the N terminus, displayed by HLA-DR 15. A minority of the clones, which have been shown to perform a cytolytic function in vitro, recognized an epitope in the tandem repeat displayed by HLA-DPw4, an uncommon restricting element. Tandem repeat epitopes required display by the β chain of DPw4 heterodimers. Thus, human T cells with different functions in vitro also recognize distinct regions of WI-1, raising the possibility that HLA restricting elements that present them could modulate immunity during blastomycosis by selection and display of WI-1 peptides.

scholarly journals PopCover-2.0. Improved Selection of Peptide Sets With Optimal HLA and Pathogen Diversity Coverage

2021 ◽  
Vol 12 ◽  
Author(s):  
Jonas Birkelund Nilsson ◽  
Alba Grifoni ◽  
Alison Tarke ◽  
Alessandro Sette ◽  
Morten Nielsen
Keyword(s):  
T Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
T Cell Epitopes ◽  
Rational Selection ◽  
Leukocyte Antigen ◽  
Pathogen Diversity ◽  
Historic Data ◽  
The Given ◽  
Selection Of

The use of minimal peptide sets offers an appealing alternative for design of vaccines and T cell diagnostics compared to conventional whole protein approaches. T cell immunogenicity towards peptides is contingent on binding to human leukocyte antigen (HLA) molecules of the given individual. HLA is highly polymorphic, and each variant typically presents a different repertoire of peptides. This polymorphism combined with pathogen diversity challenges the rational selection of peptide sets with broad immunogenic potential and population coverage. Here we propose PopCover-2.0, a simple yet highly effective method, for resolving this challenge. The method takes as input a set of (predicted) CD8 and/or CD4 T cell epitopes with associated HLA restriction and pathogen strain annotation together with information on HLA allele frequencies, and identifies peptide sets with optimal pathogen and HLA (class I and II) coverage. PopCover-2.0 was benchmarked on historic data in the context of HIV and SARS-CoV-2. Further, the immunogenicity of the selected SARS-CoV-2 peptides was confirmed by experimentally validating the peptide pools for T cell responses in a panel of SARS-CoV-2 infected individuals. In summary, PopCover-2.0 is an effective method for rational selection of peptide subsets with broad HLA and pathogen coverage. The tool is available at https://services.healthtech.dtu.dk/service.php?PopCover-2.0.

scholarly journals Design of Multi-Epitope Vaccine against SARS-CoV-2

2020 ◽  
Vol 20 (6) ◽  
pp. 185-193
Author(s):  
Irini Doytchinova ◽  
Andrey Tchorbanov
Keyword(s):  
T Cell ◽  
Human Population ◽  
Human Leukocyte ◽  
Lipid Nanoparticles ◽  
Structural Proteins ◽  
Cell Mediated Immunity ◽  
Binding Affinities ◽  
T Cell Epitopes ◽  
Epitope Vaccine ◽  
Leukocyte Antigen

AbstractThe ongoing COVID-19 pandemic requires urgently specific therapeutics and approved vaccines. Here, the four structural proteins of the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2), the causative agent of COVID-19, are screened by in-house immunoinformatic tools to identify peptides acting as potential T-cell epitopes. In order to act as an epitope, the peptide should be processed in the host cell and presented on the cell surface in a complex with the Human Leukocyte Antigen (HLA). The aim of the study is to predict the binding affinities of all peptides originating from the structural proteins of SARS-CoV-2 to 30 most frequent in the human population HLA proteins of class I and class II and to select the high binders (IC50 < 50 nM). The predicted high binders are compared to known high binders from SARS-CoV conserved in CoV-2 and 77% of them coincided. The high binders will be uploaded onto lipid nanoparticles and the multi-epitope vaccine prototype will be tested for ability to provoke T-cell mediated immunity and protection against SARS-CoV-2.

Sign in / Sign up

Export Citation Format

Share Document