scholarly journals Frequency of Interferon-Resistance Conferring Substitutions in Amino Acid Positions 70 and 91 of Core Protein of the Russian HCV 1b Isolates Analyzed in the T-Cell Epitopic Context

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
V. S. Kichatova ◽  
K. K. Kyuregyan ◽  
N. V. Soboleva ◽  
A. A. Karlsen ◽  
O. V. Isaeva ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
Immune Escape ◽  
Core Protein ◽  
Significant Proportion ◽  
In Silico Analysis ◽  
Hla Class I ◽  
T Cell Epitopes ◽  
Hla Class I Molecules ◽  
Negative Effect

Amino acid substitutions R70Q/H and L91M in HCV subtype 1b core protein can affect the response to interferon and are associated with the development of hepatocellular carcinoma. We found that the rate of R70Q/H in HCV 1b from Russia was 31.2%, similar to that in HCV strains from Asia (34.0%), higher than that in the European (18.0%, p=0.0010), but lower than that in the US HCV 1b strains (62.8%, p<0.0001). Substitution L91M was found in 80.4% of the Russian HCV 1b isolates, higher than in Asian isolates (43.8%, p<0.0001). Thus, a significant proportion of Russian HCV 1b isolates carry the unfavorable R70Q/H and/or L91M substitution. In silico analysis of the epitopic structure of the regions of substitutions revealed that both harbor clusters of T-cell epitopes. Peptides encompassing these regions were predicted to bind to a panel of HLA class I molecules, with substitutions impairing peptide recognition by HLA I molecules of the alleles prevalent in Russia. This indicates that HCV 1b with R70Q/H and L91M substitutions may have evolved as the immune escape variants. Impairment of T-cell recognition may play a part in the negative effect of these substitutions on the response to IFN treatment.

scholarly journals A Bioinformatics Approach for the Prediction of Immunogenic Properties and Structure of the SARS-COV-2 B.1.617.1 Variant Spike Protein

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Vijay Kumar Srivastava ◽  
Sanket Kaushik ◽  
Gazal Bhargava ◽  
Ajay Jain ◽  
Juhi Saxena ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
B Cell ◽  
In Silico ◽  
Tertiary Structure ◽  
In Silico Analysis ◽  
Respiratory Illness ◽  
T Cell Epitopes ◽  
S Protein ◽  
Immunogenic Properties

Background. B.1.617.1, a variant of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing respiratory illness is responsible for the second wave of COVID-19 and associated with a high incidence of infectivity and mortality. To mitigate the B.1.617.1 variant of SARS-CoV-2, deciphering the protein structure and immunological responses by employing bioinformatics tools for data mining and analysis is pivotal. Objectives. Here, an in silico approach was employed for deciphering the structure and immune function of the subunit of spike (S) protein of SARS-CoV-2 B.1.617.1 variant. Methods. The partial amino acid sequence of SARS-CoV-2 B.1.617.1 variant S protein was analyzed, and its putative secondary and tertiary structure was predicted. Immunogenic analyses including B- and T-cell epitopes, interferon-gamma (IFN-γ) response, chemokine, and protective antigens for SARS-CoV 2 S proteins were predicted using appropriate tools. Results. B.1.617.1 variant S protein sequence was found to be highly stable and amphipathic. ABCpred and CTLpred analyses led to the identification of two potential antigenic B cell and T cell epitopes with starting amino acid positions at 60 and 82 (for B cell epitopes) and 54 and 98 (for T cell epitopes) having prediction scores > 0.8 . Further, RAMPAGE tool was used for determining the allowed and disallowed regions of the three-dimensional predicted structure of SARS-CoV-2 B.1.617.1 variant S protein. Conclusion. Together, the in silico analysis revealed the predicted structure of partial S protein, immunogenic properties, and possible regions for S protein of SARS-CoV-2 and provides a valuable prelude for engineering the targeted vaccine or drug against B.1.617.1 variant of SARS-CoV-2.

scholarly journals Comparative analysis of the ex vivo IFN-gamma responses to CD8+ T cell epitopes within allelic forms of PfAMA1 in subjects with natural exposure to malaria

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257219
Author(s):  
Omarine N. Nlinwe ◽  
Ebenezer A. Ofori ◽  
Kwadwo Akyea-Mensah ◽  
Eric Kyei-Baafour ◽  
Harini Ganeshan ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
Ex Vivo ◽  
Human Leukocyte ◽  
Hla Class I ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Ifn Γ ◽  
Variant Amino Acid ◽  
Parasite Strains

Antigen polymorphisms in essential malarial antigens are a key challenge to the design and development of broadly effective malaria vaccines. The effect of polymorphisms on antibody responses is fairly well studied while much fewer studies have assessed this for T cell responses. This study investigated the effect of allelic polymorphisms in the malarial antigen apical membrane antigen 1 (AMA1) on ex vivo T cell-specific IFN-γ responses in subjects with lifelong exposure to malaria. Human leukocyte antigen (HLA) class I-restricted peptides from the 3D7 clone AMA1 were bioinformatically predicted and those with variant amino acid positions used to select corresponding allelic sequences from the 7G8, FVO, FC27 and tm284 parasite strains. A total of 91 AMA1 9-10mer peptides from the five parasite strains were identified, synthesized, grouped into 42 allele sets and used to stimulate PBMCs from seven HLA class 1-typed subjects in IFN-γ ELISpot assays. PBMCs from four of the seven subjects (57%) made positive responses to 18 peptides within 12 allele sets. Fifty percent of the 18 positive peptides were from the 3D7 parasite variant. Amino acid substitutions that were associated with IFN-γ response abrogation were more frequently found at positions 1 and 6 of the tested peptides, but substitutions did not show a clear pattern of association with response abrogation. Thus, while we show some evidence of polymorphisms affecting T cell response induction, other factors including TCR recognition of HLA-peptide complexes may also be at play.

scholarly journals Conserved T-cell epitopes predicted by bioinformatics in SARS-COV-2 variants

2021 ◽  
Author(s):  
Feiyu Lu ◽  
Shengnan Wang ◽  
Ying Wang ◽  
Yunpeng Yao ◽  
Yangeng Wang ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
Hla Class I ◽  
Amino Acid Sequences ◽  
Antigenic Peptides ◽  
T Cell Epitopes ◽  
Cell Responses ◽  
Cell Immunity ◽  
Computational Workflow ◽  
High Binding Affinity

Background: Finding conservative T cell epitopes in the proteome of numerous variants of SARS-COV-2 is required to develop T cell activating SARS-COV-2 capable of inducing T cell responses against SARS-COV-2 variants. Methods: A computational workflow was performed to find HLA restricted CD8+ and CD4+ T cell epitopes among conserved amino acid sequences across the proteome of 474727 SARS-CoV-2 strains. Results: A batch of covserved regions in the amino acid sequences were found in the proteome of the SARS-COV-2 strains. 2852 and 847 peptides were predicted to have high binding affinity to distint HLA class I and class II molecules. Among them, 1456 and 484 peptides are antigenic. 392 and 111 of the antigenic peptides were found in the conseved amino acid sequences. Among the antigenic-conserved peptides, 6 CD8+ T cell epitopes and 7 CD4+ T cell epitopes were identifed. The T cell epitopes could be presented to T cells by high-affinity HLA molecules which are encoded by the HLA alleles with high population coverage. Conclusions: The T cell epitopes are conservative, antigenic and HLA presentable, and could be constructed into SARS-COV-2 vaccines for inducing protective T cell immunity against SARS-COV-2 and their variants.

scholarly journals The pathogenicity of T cell epitopes on human Goodpasture antigen and its critical amino acid motif

2017 ◽  
Vol 21 (9) ◽  
pp. 2117-2128 ◽  
Author(s):  
Shui-yi Hu ◽  
Qiu-hua Gu ◽  
Jia Wang ◽  
Miao Wang ◽  
Xiao-yu Jia ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
T Cell Epitopes ◽  
Amino Acid Motif ◽  
Critical Amino Acid ◽  
Goodpasture Antigen

Using random forest to classify T-cell epitopes based on amino acid properties and molecular features

2013 ◽  
Vol 804 ◽  
pp. 70-75 ◽  
Author(s):  
Jian-Hua Huang ◽  
Hua-Lin Xie ◽  
Jun Yan ◽  
Hong-Mei Lu ◽  
Qing-Song Xu ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
Random Forest ◽  
T Cell Epitopes ◽  
Acid Properties ◽  
Molecular Features ◽  
Amino Acid Properties

scholarly journals Extensive Polymorphism and Evidence of Immune Selection in a Highly Dominant Antigen Recognized by Bovine CD8 T Cells Specific for Theileria annulata

2011 ◽  
Vol 79 (5) ◽  
pp. 2059-2069 ◽  
Author(s):  
Niall D. MacHugh ◽  
William Weir ◽  
Alison Burrells ◽  
Regina Lizundia ◽  
Simon P. Graham ◽  
...  
Keyword(s):  
Amino Acid ◽  
T Cell ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Theileria Annulata ◽  
T Cell Epitopes ◽  
Major Histocompatibility Complex Haplotype ◽  
Content Type ◽  
Cell Responses ◽  
Restricted Epitope

ABSTRACTAlthough parasite strain-restricted CD8 T cell responses have been described for several protozoa, the precise role of antigenic variability in immunity is poorly understood. The tick-borne protozoan parasiteTheileria annulatainfects leukocytes and causes an acute, often fatal lymphoproliferative disease in cattle. Building on previous evidence of strain-restricted CD8 T cell responses toT. annulata, this study set out to identify and characterize the variability of the target antigens. Three antigens were identified by screening expressed parasite cDNAs with specific CD8 T cell lines. In cattle expressing the A10 class I major histocompatibility complex haplotype, A10-restricted CD8 T cell responses were shown to be focused entirely on a single dominant epitope in one of these antigens (Ta9). Sequencing of the Ta9 gene from field isolates ofT. annulatademonstrated extensive sequence divergence, resulting in amino acid polymorphism within the A10-restricted epitope and a second A14-restricted epitope. Statistical analysis of the allelic sequences revealed evidence of positive selection for amino acid substitutions within the region encoding the CD8 T cell epitopes. Sequence differences in the A10-restricted epitope were shown to result in differential recognition by individual CD8 T cell clones, while clones also differed in their ability to recognize different alleles. Moreover, the representation of these clonal specificities within the responding CD8 T cell populations differed between animals. As well as providing an explanation for incomplete protection observed after heterologous parasite challenge of vaccinated cattle, these results have important implications for the choice of antigens for the development of novel subunit vaccines.

scholarly journals Public T-cell epitopes shared among SARS-CoV-2 variants are presented on prevalent HLA class I alleles

2021 ◽  
Author(s):  
Saskia Meyer ◽  
Isaac Blaas ◽  
Ravi Chand Bollineni ◽  
Marina Delic-Sarac ◽  
Trung T Tran ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
Hla Class I ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Class I ◽  
T Cell Epitopes ◽  
Low Frequencies ◽  
Cell Responses

T-cell epitopes with broad population coverage may form the basis for a new generation of SARS-CoV-2 vaccines. However, published studies on immunoprevalence are limited by small test cohorts, low frequencies of antigen-specific cells and lack of data correlating eluted HLA ligands with T-cell responsiveness. Here, we investigate CD8 T-cell responses to 48 peptides eluted from prevalent HLA alleles, and an additional 84 predicted binders, in a large cohort of convalescents (n=83) and pre-pandemic control samples (n=19). We identify nine conserved SARS-CoV-2 specific epitopes restricted by four of the most prevalent HLA class I alleles in Caucasians, to which responding CD8 T cells are detected in 70-100% of convalescents expressing the relevant HLA allele, including two novel epitopes. We find a strong correlation between immunoprevalence and immunodominance. Using a new algorithm, we predict that a vaccine including these epitopes would induce a T cell response in 83% of Caucasians. Significance Statement: Vaccines that induce broad T-cell responses may boost immunity as protection from current vaccines against SARS-CoV-2 is waning. From a manufacturing standpoint, and to deliver the highest possible dose of the most immunogenic antigens, it is rational to limit the number of epitopes to those inducing the strongest immune responses in the highest proportion of individuals in a population. Our data show that the CD8 T cell response to SARS-CoV-2 is more focused than previously believed. We identify nine conserved SARS-CoV-2 specific CD8 T cell epitopes restricted by four of the most prevalent HLA class I alleles in Caucasians and demonstrate that seven of these are endogenously presented.

scholarly journals Discovery and Selection of Hepatitis B Virus-Derived T Cell Epitopes for Global Immunotherapy Based on Viral Indispensability, Conservation, and HLA-Binding Strength

2019 ◽  
Vol 94 (7) ◽  
Author(s):  
Monique T. A. de Beijer ◽  
Diahann T. S. L. Jansen ◽  
Yingying Dou ◽  
Wim J. E. van Esch ◽  
Juk Yee Mok ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
T Cell ◽  
Hepatitis B ◽  
Viral Replication ◽  
Immune Escape ◽  
The Novel ◽  
T Cell Epitopes ◽  
Infected Population ◽  
B Virus ◽  
Hla Binding

ABSTRACT Immunotherapy represents an attractive option for the treatment of chronic hepatitis B virus (HBV) infection. The HBV proteins polymerase (Pol) and HBx are of special interest for antigen-specific immunotherapy because they are essential for viral replication and have been associated with viral control (Pol) or are still expressed upon viral DNA integration (HBx). Here, we scored all currently described HBx- and Pol-derived epitope sequences for viral indispensability and conservation across all HBV genotypes. This yielded 7 HBx-derived and 26 Pol-derived reported epitopes with functional association and high conservation. We subsequently predicted novel HLA-binding peptides for 6 HLA supertypes prevalent in HBV-infected patients. Potential epitopes expected to be the least prone to immune escape were subjected to a state-of-the-art in vitro assay to validate their HLA-binding capacity. Using this method, a total of 13 HLA binders derived from HBx and 33 binders from Pol were identified across HLA types. Subsequently, we demonstrated interferon gamma (IFN-γ) production in response to 5 of the novel HBx-derived binders and 17 of the novel Pol-derived binders. In addition, we validated several infrequently described epitopes. Collectively, these results specify a set of highly potent T cell epitopes that represent a valuable resource for future HBV immunotherapy design. IMPORTANCE Multiple HBV-derived T cell epitopes have been reported, which can be useful in a therapeutic vaccination strategy. However, these epitopes are largely restricted to HLA-A*02, which is not dominantly expressed in populations with high HBV prevalence. Thus, current epitopes are falling short in the development of a global immunotherapeutic approach. Therefore, we aimed to identify novel epitopes for 6 HLA supertypes most prevalent in the infected population. Moreover, established epitopes might not all be equally effective as they can be subject to different levels of immune escape. It is therefore important to identify targets that are crucial in viral replication and conserved in the majority of the infected population. Here, we applied a stringent selection procedure to compose a combined overview of existing and novel HBV-derived T cell epitopes most promising for viral eradication. This set of T cell epitopes now lays the basis for the development of globally effective HBV antigen-specific immunotherapies.

scholarly journals Results of a randomized, double-blind phase II clinical trial of NY-ESO-1 vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in participants with high-risk resected melanoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000410
Author(s):  
Jonathan S Cebon ◽  
Martin Gore ◽  
John F Thompson ◽  
Ian D Davis ◽  
Grant A McArthur ◽  
...  
Keyword(s):  
New York ◽  
High Risk ◽  
Phase Ii ◽  
Immune Escape ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
Double Positive ◽  
Double Blind ◽  
Hla Class I Molecules

BackgroundTo compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence.MethodsParticipants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity.ResultsThe ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4+and CD8+responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)+/Human Leukocyte Antigen (HLA) class I+double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants.ConclusionsThe vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse.

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