High polymorphism rates in well-known T cell epitopes restricted by protective HLA alleles during HIV infection are associated with rapid disease progression in early-infected MSM in China

2019 ◽  
Vol 208 (2) ◽  
pp. 239-251 ◽  
Author(s):  
Chuan He ◽  
Xiaoxu Han ◽  
Hui Zhang ◽  
Fanming Jiang ◽  
Minghui An ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Disease Progression ◽  
T Cell Epitopes ◽  
Rapid Disease Progression ◽  
Hla Alleles

scholarly journals The combination of CXCL9, CXCL10 and CXCL11 levels during primary HIV infection predicts HIV disease progression

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Xiaowan Yin ◽  
Zhuo Wang ◽  
Tong Wu ◽  
Meichen Ma ◽  
Zining Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Cell Count ◽  
Disease Progression ◽  
Risk Score ◽  
Point Group ◽  
Clinical Information ◽  
Hiv Disease ◽  
Set Point ◽  
Primary Hiv Infection

Abstract Background Chemokines are small chemotactic cytokines involved in inflammation, cell migration, and immune regulation in both physiological and pathological contexts. Here, we investigated the profile of chemokines during primary HIV infection (PHI). Methods Fifty-four participants with blood samples before and during HIV infection and clinical information available were selected from an HIV-negative man who have sex with men (MSM) prospective cohort. Thirty chemokines and 10 cytokines were measured pre- and post-HIV infection in the same individuals using a Bio-Plex Pro™ Human Chemokine Panel. Results Levels of 18 chemokines/cytokines changed significantly during PHI relative to pre-HIV infection levels; 14 were up-regulated and 4 down-regulated. Among them, CXCL9, CXCL10, and CXCL11 were the most prominently raised. Levels of CXCL9 and CXCL10 were much higher in the high-set point group (log viral load (lgVL) ≥ 4.5) than those in the low-set point group (lgVL < 4.5) and levels of CXCL9, CXCL10, and CXCL11 were higher in the low-CD4+ T-cell count group (CD4+ T-cell count ≥ 500). A formula to predict HIV disease progression using a combination panel comprising CXCL9, CXCL10, and CXCL11 was developed, where risk score = 0.007 × CXCL9 + 0.004 × CXCL10 − 0.033 × CXCL11 − 1.724, with risk score values higher than the cutoff threshold (0.5211) indicating more rapid HIV disease progression. Conclusions A panel of plasma CXCL9, CXCL10, and CXCL11 measured during primary HIV-1 infection could predict long-term HIV disease prognosis in an MSM group and has potential as a novel biomarker in the clinic.

scholarly journals T-CoV: a comprehensive portal of HLA-peptide interactions affected by SARS-CoV-2 mutations

2021 ◽  
Author(s):  
Stepan Nersisyan ◽  
Anton Zhiyanov ◽  
Maxim Shkurnikov ◽  
Alexander Tonevitsky
Keyword(s):  
T Cell ◽  
Hla Class I ◽  
Binding Affinities ◽  
T Cell Epitopes ◽  
Hla Alleles ◽  
Cell Responses ◽  
Hla Genotypes ◽  
Peptide Interactions ◽  
The Uk ◽  
Hla Molecules

Rapidly appearing SARS-CoV-2 mutations can affect T cell epitopes, which can help the virus to evade either CD8 or CD4 T-cell responses. We developed T-cell COVID-19 Atlas (T-CoV, https://t-cov.hse.ru) - the comprehensive web portal, which allows one to analyze how SARS-CoV-2 mutations alter the presentation of viral peptides by HLA molecules. The data are presented for common virus variants and the most frequent HLA class I and class II alleles. Binding affinities of HLA molecules and viral peptides were assessed with accurate in silico methods. The obtained results highlight the importance of taking HLA alleles diversity into account: mutation-mediated alterations in HLA-peptide interactions were highly dependent on HLA alleles. For example, we found that the essential number of peptides tightly bound to HLA-B*07:02 in the reference Wuhan variant ceased to be tight binders for the Indian (Delta) and the UK (Alpha) variants. In summary, we believe that T-CoV will help researchers and clinicians to predict the susceptibility of individuals with different HLA genotypes to infection with variants of SARS-CoV-2 and/or forecast its severity.

scholarly journals Computational Identification and Characterization of a Promiscuous T-Cell Epitope on the Extracellular Protein 85B ofMycobacteriumspp. for Peptide-Based Subunit Vaccine Design

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Md. Saddam Hossain ◽  
Abul Kalam Azad ◽  
Parveen Afroz Chowdhury ◽  
Mamoru Wakayama
Keyword(s):  
Molecular Docking ◽  
T Cell ◽  
Cell Epitope ◽  
Docking Simulation ◽  
Vaccine Design ◽  
Extracellular Protein ◽  
T Cell Epitope ◽  
T Cell Epitopes ◽  
Hla Alleles ◽  
Mhc Molecules

Tuberculosis (TB) is a reemerging disease that remains as a leading cause of morbidity and mortality in humans. To identify and characterize a T-cell epitope suitable for vaccine design, we have utilized the Vaxign server to assess all antigenic proteins ofMycobacteriumspp. recorded to date in the Protegen database. We found that the extracellular protein 85B displayed the most robust antigenicity among the proteins identified. Computational tools for identifying T-cell epitopes predicted an epitope, 181-QQFIYAGSLSALLDP-195, that could bind to at least 13 major histocompatibility complexes, revealing the promiscuous nature of the epitope. Molecular docking simulation demonstrated that the epitope could bind to the binding groove of MHC II and MHC I molecules by several hydrogen bonds. Molecular docking analysis further revealed that the epitope had a distinctive binding pattern to all DRB1 and A and B series of MHC molecules and presented almost no polymorphism in its binding site. Moreover, using “Allele Frequency Database,” we checked the frequency of HLA alleles in the worldwide population and found a higher frequency of both class I and II HLA alleles in individuals living in TB-endemic regions. Our results indicate that the identified peptide might be a universal candidate to produce an efficient epitope-based vaccine for TB.

Protective HLA Alleles Recruit Biased and Largely Similar Antigen-Specific T Cell Repertoires across Different Outcomes in HIV Infection

2021 ◽  
pp. ji2001145
Author(s):  
Dan Koning ◽  
Esther D. Quakkelaar ◽  
Ingrid M. M. Schellens ◽  
Eric Spierings ◽  
Debbie van Baarle
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Hla Alleles

Selective HLA Restriction Permits the Evaluation and Interpretation of Immunogenic Breadth at Comparable Levels to Autologous HLA

2020 ◽  
Author(s):  
Jonathan Hare ◽  
Andrew Fiore-Gartland ◽  
Edward McGowan ◽  
Rachel Rosenthal ◽  
Eric Hunter ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Epitopes ◽  
Hla Alleles ◽  
Hla Restriction ◽  
Experimental Strategies ◽  
Targeted Approach

Existing approaches to identifying predictive T-cell epitopes have traditionally utilized either 2-digit HLA super-families or more commonly autologous HLA alleles to facilitate the predictions, but frequently they may not consider their representation within a population. Here we propose a modification to this concept whereby subsets of individuals are selected for their specific HLA allele profiles and the representation they provide within a given population. Using this targeted approach to HLA selection and the linkages to specific individuals may enable the design of restricted experimental strategies.

scholarly journals Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8+T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression

2015 ◽  
Vol 89 (7) ◽  
pp. 3723-3736 ◽  
Author(s):  
Kiera L. Clayton ◽  
Matthew B. Douglas-Vail ◽  
A. K. M. Nur-ur Rahman ◽  
Karyn E. Medcalf ◽  
Irene Y. Xie ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Disease Progression ◽  
Human Plasma ◽  
Soluble Form ◽  
Hiv Disease ◽  
Cell Exhaustion ◽  
Domain 3 ◽  
Chronic Hiv Infection

ABSTRACTChronic HIV infection results in a loss of HIV-specific CD8+T cell effector function, termed “exhaustion,” which is mediated, in part, by the membrane coinhibitory receptor T cell immunoglobulin mucin domain-3 (Tim-3). Like many other receptors, a soluble form of this protein has been described in human blood plasma. However, soluble Tim-3 (sTim-3) is poorly characterized, and its role in HIV disease is unknown. Here, we show that Tim-3 is shed from the surface of responding CD8+T cells by the matrix metalloproteinase ADAM10, producing a soluble form of the coinhibitory receptor. Despite previous reports in the mouse model, no alternatively spliced, soluble form of Tim-3 was observed in humans. Shed sTim-3 was found in human plasma and was significantly elevated during early and chronic untreated HIV infection, but it was not found differentially modulated in highly active antiretroviral therapy (HAART)-treated HIV-infected subjects or in elite controllers compared to HIV-uninfected subjects. Plasma sTim-3 levels were positively correlated with HIV load and negatively correlated with CD4 counts. Thus, plasma sTim-3 shedding correlated with HIV disease progression. Despite these correlations, we found that shedding Tim-3 did not improve the function of CD8+T cells in terms of gamma interferon production or prevent their apoptosis through galectin-9. Further characterization studies of sTim-3 function are needed to understand the contribution of sTim-3 in HIV disease pathogenesis, with implications for novel therapeutic interventions.IMPORTANCEDespite the overall success of HAART in slowing the progression to AIDS in HIV-infected subjects, chronic immune activation and T cell exhaustion contribute to the eventual deterioration of the immune system. Understanding these processes will aid in the development of interventions and therapeutics to be used in combination with HAART to slow or reverse this deterioration. Here, we show that a soluble form of T cell exhaustion associated coinhibitory molecule 3, sTim-3, is shed from the surface of T cells. Furthermore, sTim-3 is elevated in the plasma of treatment-naive subjects with acute or chronic HIV infection and is associated with markers of disease progression. This is the first study to characterize sTim-3 in human plasma, its source, and mechanism of production. While it is still unclear whether sTim-3 contributes to HIV pathogenesis, sTim-3 may represent a new correlate of HIV disease progression.

scholarly journals Th17 and Th17/Treg ratio at early HIV infection associate with protective HIV-specific CD8+ T-cell responses and disease progression

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Juliana Falivene ◽  
Yanina Ghiglione ◽  
Natalia Laufer ◽  
María Eugenia Socías ◽  
María Pía Holgado ◽  
...  
Keyword(s):  
T Cell ◽  
Hiv Infection ◽  
Disease Progression ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses

scholarly journals CD8+ T-Cell Response-Associated Evolution of Hepatitis B Virus Core Protein and Disease Progress

2018 ◽  
Vol 92 (17) ◽  
Author(s):  
Yu Zhang ◽  
Yan Wu ◽  
Mengmeng Deng ◽  
Dongping Xu ◽  
Xiaodong Li ◽  
...  
Keyword(s):  
T Cell ◽  
Hepatitis B ◽  
Disease Progression ◽  
Core Protein ◽  
T Cell Response ◽  
Clinical Parameters ◽  
T Cell Epitopes ◽  
Terminal Portion ◽  
Immune Pressure ◽  
B Virus

ABSTRACT Under the immune pressure of cytotoxic T cells (CTLs), hepatitis B virus (HBV) evolves to accumulate mutations more likely within epitopes to evade immune detection. However, little is known about the specific patterns of the immune pressure-associated HBV mutation of T-cell epitopes and their link to disease progression. Here, we observed a correlation of the accumulated variants on HBV core protein (HBc) with the disease severity of HBV infection. Further analysis indicated that these substitutions were mostly located within CD8+ T-cell epitopes of HBc protein, which were systematically screened and identified in an unbiased manner in our study. From individual peptide level to the human leukocyte antigen I (HLA-I)-restricted population level, we elucidated that the mutations in these well-defined HLA-I-restricted T-cell epitopes significantly decreased antiviral activity-specific CTLs and were positively associated with clinical parameters and disease progression in HBV-infected patients. The molecular pattern for viral epitope variations based on the sequencing of 105 HBV virus genomes indicated that the C-terminal portion (Pc), especially the Pc-1 and Pc-2 positions, have the highest mutation rates. Further structural analysis of HLA-A*02 complexed to diverse CD8+ T-cell epitopes revealed that the highly variable C-terminal bulged peak of M-shaped HBc-derived epitopes are solvent exposed, and most of the CDR3βs of the T-cell receptor hover over them. These data shed light on the molecular and immunological mechanisms of T-cell immunity-associated viral evolution in hepatitis B progression, which is beneficial for designing immunotherapies and vaccines. IMPORTANCE The specific patterns of sequence polymorphisms of T-cell epitopes and the immune mechanisms of the HBV epitope mutation-linked disease progression are largely unclear. In this study, we systematically evaluated the contribution of CD8+ T cells to the disease progress-associated evolution of HBV. By evaluation of patient T-cell responses based on the peptide repertoire, we comprehensively characterized the association of clinical parameters in chronic hepatitis B with the antiviral T-cell response-associated mutations of the viruses from the single-epitope level to the overall HLA-I-restricted peptide levels. Furthermore, we investigated the molecular basis of the HLA-A2-restricted peptide immune escape and found that the solvent-exposed C-terminal portion of the epitopes is highly variable under CDR3β recognition. Our work may provide a comprehensive evaluation of viral mutations impacted by the host CTL response in HBV disease progression in the context of the full repertoire of HBc-derived epitopes.

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