INTRAHOST EVOLUTION OF THE HIV-2 CAPSID CORRELATES WITH PROGRESSION TO AIDS

Background: HIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 p26 amino acid variations are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific CTL responses common in slower disease progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. We therefore aimed to determine if intrahost evolution of HIV-2 p26 is associated with disease progression. Methods: Twelve treatment-naive, HIV-2 mono-infected participants from the Guinea-Bissau Police cohort with longitudinal CD4+ T cell data and clinical follow-up were included in the analysis. CD4% change over time was analysed via linear regression models to stratify participants into relative faster and slower disease progressor groups. Gag amplicons of 735 nucleotides which spanned the p26 region were amplified by PCR and sequenced. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Amino acid polymorphisms were mapped to existing p26 protein structures. Results: In total, 369 heterochronous HIV-2 p26 sequences from 12 male patients with a median age of 30 (IQR: 28-37) years at enrolment were analysed. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10-3 versus 1.4x10-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Virus evolutionary rates were higher in faster than slower progressors - synonymous rates: 4.6x10-3 vs. 2.3x10-3; and nonsynonymous rates: 6.9x10-4 vs. 2.7x10-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (rho = -0.8, P=0.02), but not CD4% level. However, Bayes factor (BF) testing indicated that the association between evolutionary rates and CD4% kinetics was supported by weak evidence (BF=0.5). The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5 alpha/p26 hexamer interface surface. Conclusions: Faster p26 evolutionary rates were associated with faster progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate the HIV-2 p26 may be an attractive vaccine or therapeutic target.

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

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.13134 ◽

2017 ◽

Vol 21 (9) ◽

pp. 2117-2128 ◽

Cited By ~ 4

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

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

Analytica Chimica Acta ◽

10.1016/j.aca.2013.10.003 ◽

2013 ◽

Vol 804 ◽

pp. 70-75 ◽

Cited By ~ 11

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

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

Infection and Immunity ◽

10.1128/iai.01285-10 ◽

2011 ◽

Vol 79 (5) ◽

pp. 2059-2069 ◽

Cited By ~ 26

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.

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Sequence Diversity in the pe_pgrs Genes of Mycobacterium tuberculosis Is Independent of Human T Cell Recognition

mBio ◽

10.1128/mbio.00960-13 ◽

2014 ◽

Vol 5 (1) ◽

Cited By ~ 60

Author(s):

Richard Copin ◽

Mireia Coscollá ◽

Salome N. Seiffert ◽

Graham Bothamley ◽

Jayne Sutherland ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

T Cell ◽

Sequence Variation ◽

Large Family ◽

Sequence Diversity ◽

Cell Recognition ◽

T Cell Epitopes ◽

Content Type ◽

T Cell Recognition ◽

Human T Cell

ABSTRACTTheMycobacterium tuberculosisgenome includes the large family ofpe_pgrsgenes, whose functions are unknown. Because of precedents in other pathogens in which gene families showing high sequence variation are involved in antigenic variation, a similar role has been proposed for thepe_pgrsgenes. However, the impact of immune selection onpe_pgrsgenes has not been examined. Here, we sequenced 27pe_pgrsgenes in 94 clinical strains from five phylogenetic lineages of theM. tuberculosiscomplex (MTBC). We found thatpe_pgrsgenes were overall more diverse than the remainder of the MTBC genome, but individual members of the family varied widely in their nucleotide diversity and insertion/deletion (indel) content: some were more, and others were much less, diverse than the genome average. Individualpe_pgrsgenes also differed in the ratio of nonsynonymous to synonymous mutations, suggesting that different selection pressures act on individualpe_pgrsgenes. Using bioinformatic methods, we tested whether sequence diversity inpe_pgrsgenes might be selected by human T cell recognition, the major mechanism of adaptive immunity to MTBC. We found that the large majority of predicted human T cell epitopes were confined to the conserved PE domain and experimentally confirmed the antigenicity of this domain in tuberculosis patients. In contrast, despite being genetically diverse, the PGRS domains harbored few predicted T cell epitopes. These results indicate that human T cell recognition is not a significant force driving sequence diversity inpe_pgrsgenes, which is consistent with the previously reported conservation of human T cell epitopes in the MTBC.IMPORTANCERecognition ofMycobacterium tuberculosisantigens by T lymphocytes is known to be important for immune protection against tuberculosis, but it is unclear whether human T cell recognition drives antigenic variation inM. tuberculosis. We previously discovered that the known human T cell epitopes in theM. tuberculosiscomplex are highly conserved, but we hypothesized that undiscovered epitopes with naturally occurring sequence variants might exist. To test this hypothesis, we examined thepe_pgrsgenes, a large family of genes that has been proposed to function in immune evasion byM. tuberculosis. We found that thepe_pgrsgenes exhibit considerable sequence variation, but the regions containing T cell epitopes and the regions of variation are distinct. These findings confirm that the majority of human T cell epitopes ofM. tuberculosisare highly conserved and indicate that selection forces other than T cell recognition drive sequence variation in thepe_pgrsgenes.

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Thyrotropin-Receptor and Thyroid Peroxidase-Specific T Cell Clones and Their Cytokine Profile in Autoimmune Thyroid Disease1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.82.11.4336 ◽

1997 ◽

Vol 82 (11) ◽

pp. 3655-3663

Author(s):

Maria Elena Fisfalen ◽

Ellen M. Palmer ◽

Gijs A. van Seventer ◽

Keyoumars Soltani ◽

Yoshikuni Sawai ◽

...

Keyword(s):

Amino Acid ◽

T Cell ◽

Thyroid Tissue ◽

Cytokine Profile ◽

Thyroid Peroxidase ◽

Amino Acid Residues ◽

T Cell Epitopes ◽

T Cell Clones ◽

Cell Clones ◽

Ifn Γ

We studied the cytokine profile and the immune responses to thyroid antigens of specific T cell clones (TCC) isolated from patients with Hashimoto’s thyroiditis (HT) and Graves’ disease (GD). Antigen-specific TCC were reactive to thyroid peroxidase (TPO), thyroglobulin (Tg) or human recombinant TSH-receptor extracellular domain (TSH-R), and/or their respective peptides. Of the 43 clones derived from HT patients, 65% were reactive to TPO, and 59% of the 32 clones derived from GD patients were reactive to TSH-R. TPO epitopes 100–119 and 625–644 were recognized by 75% of HT-derived clones, whereas TSH-R epitopes 158–176, 207–222, and 343–362/357–376 were recognized by 85% of GD-derived TCC. The TCC were classified according to their cytokine profile into T helper cell (Th)0 [secreting interleukin (IL)-4, IL-5, interferon (IFN)-γ], Th1 (secreting IFN-γ) and Th2 (secreting IL-4 and/or IL-5). Tumor necrosis factor-β and IL-10 were produced by all subsets. The specific TCC were predominantly Th1-like cells in HT, and were Th0- and Th1-like cells in GD. Fifty three percent of Th0 clones were derived from GD patients and were reactive to TSH-R, whereas 50% of Th1 clones were derived from HT patients and were reactive to TPO or Tg. Most Th2 clones (82%) were reactive to TPO and were established from peripheral blood. All these clones produced IL-5, and 64% produced IL-4 and IL-10. Interestingly, IFN-γ was highly produced by TPO- or Tg-specific clones established from HT thyroid tissue. These results confirm at the clonal level our previous studies regarding T cell epitopes on TPO and TSH-R molecules and support the concept that immunodominant T cell epitopes are located on amino acid residues 100–119 and 625–644 of TPO in HT and amino acid residues 158–176, 207–222 and 343–362/357–376 of TSH-R in GD. Our studies also demonstrate that thyroid-specific T cells can be classified into Th0, Th1, and Th2 subsets. TPO- or Tg-specific clones with Th1 phenotype appear to be involved in the pathogenesis of HT, mediating thyroid tissue destruction, whereas TSH-R clones with Th0 phenotype may induce thyroid-stimulating autoantibodies in GD.

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Molecular Mimicry Map (3M) of SARS-CoV-2: Prediction of potentially immunopathogenic SARS-CoV-2 epitopes via a novel immunoinformatic approach

10.1101/2020.11.12.344424 ◽

2020 ◽

Author(s):

Hyunsu An ◽

Jihwan Park

Keyword(s):

T Cell ◽

Autoimmune Diseases ◽

Web Application ◽

Molecular Mimicry ◽

Sequence Similarity ◽

Protein Structures ◽

Cross Reactivity ◽

T Cell Epitopes ◽

B Cell Epitopes ◽

Human Proteins

ABSTRACTCurrently, more than 33 million peoples have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more than a million people died from coronavirus disease 2019 (COVID-19), a disease caused by the virus. There have been multiple reports of autoimmune and inflammatory diseases following SARS-CoV-2 infections. There are several suggested mechanisms involved in the development of autoimmune diseases, including cross-reactivity (molecular mimicry). A typical workflow for discovering cross-reactive epitopes (mimotopes) starts with a sequence similarity search between protein sequences of human and a pathogen. However, sequence similarity information alone is not enough to predict cross-reactivity between proteins since proteins can share highly similar conformational epitopes whose amino acid residues are situated far apart in the linear protein sequences. Therefore, we used a hidden Markov model-based tool to identify distant viral homologs of human proteins. Also, we utilized experimentally determined and modeled protein structures of SARS-CoV-2 and human proteins to find homologous protein structures between them. Next, we predicted binding affinity (IC50) of potentially cross-reactive T-cell epitopes to 34 MHC allelic variants that have been associated with autoimmune diseases using multiple prediction algorithms. Overall, from 8,138 SARS-CoV-2 genomes, we identified 3,238 potentially cross-reactive B-cell epitopes covering six human proteins and 1,224 potentially cross-reactive T-cell epitopes covering 285 human proteins. To visualize the predicted cross-reactive T-cell and B-cell epitopes, we developed a web-based application “Molecular Mimicry Map (3M) of SARS-CoV-2” (available at https://ahs2202.github.io/3M/). The web application enables researchers to explore potential cross-reactive SARS-CoV-2 epitopes alongside custom peptide vaccines, allowing researchers to identify potentially suboptimal peptide vaccine candidates or less ideal part of a whole virus vaccine to design a safer vaccine for people with genetic and environmental predispositions to autoimmune diseases. Together, the computational resources and the interactive web application provide a foundation for the investigation of molecular mimicry in the pathogenesis of autoimmune disease following COVID-19.

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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

Journal of Immunology Research ◽

10.1155/2018/7685371 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 6

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.

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A 10-Amino-Acid Linear Sequence of VP1 of Foot and Mouth Disease Virus Containing B- and T-Cell Epitopes Induces Protection in Mice

Virology ◽

10.1006/viro.1995.1519 ◽

1995 ◽

Vol 212 (2) ◽

pp. 614-621 ◽

Cited By ~ 40

Author(s):

P. Zamorano ◽

A. Wigdorovitz ◽

M. Perez-Filgueira ◽

C. Carrillo ◽

J.M. Escribano ◽

...

Keyword(s):

Amino Acid ◽

T Cell ◽

Disease Virus ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

T Cell Epitopes ◽

Linear Sequence ◽

Mouth Disease Virus ◽

Foot And Mouth

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Cellular immune selection with hepatitis C virus persistence in humans

Journal of Experimental Medicine ◽

10.1084/jem.20050121 ◽

2005 ◽

Vol 201 (11) ◽

pp. 1741-1752 ◽

Cited By ~ 210

Author(s):

Andrea L. Cox ◽

Timothy Mosbruger ◽

Qing Mao ◽

Zhi Liu ◽

Xiao-Hong Wang ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Viral Escape ◽

Sequence Evolution ◽

T Cell Epitopes ◽

Cell Responses ◽

Cellular Immune

Hepatitis C virus (HCV) infection frequently persists despite substantial virus-specific cellular immune responses. To determine if immunologically driven sequence variation occurs with HCV persistence, we coordinately analyzed sequence evolution and CD8+ T cell responses to epitopes covering the entire HCV polyprotein in subjects who were followed prospectively from before infection to beyond the first year. There were no substitutions in T cell epitopes for a year after infection in a subject who cleared viremia. In contrast, in subjects with persistent viremia and detectable T cell responses, we observed substitutions in 69% of T cell epitopes, and every subject had a substitution in at least one epitope. In addition, amino acid substitutions occurred 13-fold more often within than outside T cell epitopes (P < 0.001, range 5–38). T lymphocyte recognition of 8 of 10 mutant peptides was markedly reduced compared with the initial sequence, indicating viral escape. Of 16 nonenvelope substitutions that occurred outside of known T cell epitopes, 8 represented conversion to consensus (P = 0.015). These findings reveal two distinct mechanisms of sequence evolution involved in HCV persistence: viral escape from CD8+ T cell responses and optimization of replicative capacity.

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