Artículos de revistas: "Epitopes, B-Lymphocyte"

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Lu, Y. J., D. Sh Chen, W. T. Hao, H. W. Xu, Y. W. Zhang, F. F. Sun y W. Pan. "In silico characterization of Echinococcus granulosus paramyosin nucleotide sequence for the development of epitope vaccine against cystic echinococcosis". Helminthologia 54, n.º 4 (1 de diciembre de 2017): 275–83. http://dx.doi.org/10.1515/helm-2017-0041.

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Summary The paramyosin (Pmy) protein has been presented as a potential vaccine candidate against Schistosoma spp. However, it remains elusive whether it works in controlling cystic echinococcosis (CE), which is caused by the larval stages of Echinococcus granulosus (E. granulosus). This study investigated the characteristics of E. granulosus Pmy (EgPmy) using in silico analysis and evaluated its potential as an epitope vaccine. The secondary structure was predicted by SOPMA software and linear B-cell epitopes were screened by the Kolaskar and Tongaonkar’s method on IEBD while conformational B-cell epitopes were predicted by the Ellipro. Additionally, the epitopes of cytotoxic T lymphocyte (CTL) were analyzed by the NetCTL-1.2 server. The results showed that α-helices, extended strands, random coils and β-turns accounted for 84.82 %, 6.60 %, 5.56 % and 3.01 % in EgPmy’s secondary structure, respectively. A total of 29 linear B-cell epitopes and 6 conformational epitopes were identified together with 25 CTL epitopes. The CTL epitope 709KLEEAEAFA717 showed a high potential to elicit CTL response. These results suggested that EgPmy has a strong immunogenicity, which could serve as a reference for the development of EgPmy-based epitope vaccine against CE.

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He, Shudong, Jinlong Zhao, Walid Elfalleh, Mohamed Jemaà, Hanju Sun, Xianbao Sun, Mingming Tang, Qian He, Zeyu Wu y Florian Lang. "In Silico Identification and in Vitro Analysis of B and T-Cell Epitopes of the Black Turtle Bean (Phaseolus Vulgaris L.) Lectin". Cellular Physiology and Biochemistry 49, n.º 4 (2018): 1600–1614. http://dx.doi.org/10.1159/000493496.

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Background/Aims: The incidence of lectin allergic disease is increasing in recent decades, and definitive treatment is still lacking. Identification of B and T-cell epitopes of allergen will be useful in understanding the allergen antibody responses as well as aiding in the development of new diagnostics and therapy regimens for lectin poisoning. In the current study, we mainly addressed these questions. Methods: Three-dimensional structure of the lectin from black turtle bean (Phaseolus vulgaris L.) was modeled using the structural template of Phytohemagglutinin from P. vulgaris (PHA-E, PDB ID: 3wcs.1.A) with high identity. The B and T-cell epitopes were screened and identified by immunoinformatics and subsequently validated by ELISA, lymphocyte proliferation and cytokine profile analyses. Results: Seven potential B-cell epitopes (B1 to B7) were identified by sequence and structure based methods, while three T-cell epitopes (T1 to T3) were identified by the predictions of binding score and inhibitory concentration. The epitope peptides were synthesized. Significant IgE binding capability was found in B-cell epitopes (B2, B5, B6 and B7) and T2 (a cryptic B-cell epitope). T1 and T2 induced significant lymphoproliferation, and the release of IL-4 and IL-5 cytokine confirmed the validity of T-cell epitope prediction. Abundant hydrophobic amino acids were found in B-cell epitope and T-cell epitope regions by amino acid analysis. Positively charged amino acids, such as His residue, might be more favored for B-cell epitope. Conclusion: The present approach can be applied for the identification of epitopes in novel allergen proteins and thus for designing diagnostics and therapies in lectin allergy.

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Depla, Erik, Annegret Van der Aa, Brian D. Livingston, Claire Crimi, Koen Allosery, Veronique De Brabandere, Jonathan Krakover et al. "Rational Design of a Multiepitope Vaccine Encoding T-Lymphocyte Epitopes for Treatment of Chronic Hepatitis B Virus Infections". Journal of Virology 82, n.º 1 (17 de octubre de 2007): 435–50. http://dx.doi.org/10.1128/jvi.01505-07.

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ABSTRACT Protein sequences from multiple hepatitis B virus (HBV) isolates were analyzed for the presence of amino acid motifs characteristic of cytotoxic T-lymphocyte (CTL) and helper T-lymphocyte (HTL) epitopes with the goal of identifying conserved epitopes suitable for use in a therapeutic vaccine. Specifically, sequences bearing HLA-A1, -A2, -A3, -A24, -B7, and -DR supertype binding motifs were identified, synthesized as peptides, and tested for binding to soluble HLA. The immunogenicity of peptides that bound with moderate to high affinity subsequently was assessed using HLA transgenic mice (CTL) and HLA cross-reacting H-2bxd (BALB/c × C57BL/6J) mice (HTL). Through this process, 30 CTL and 16 HTL epitopes were selected as a set that would be the most useful for vaccine design, based on epitope conservation among HBV sequences and HLA-based predicted population coverage in diverse ethnic groups. A plasmid DNA-based vaccine encoding the epitopes as a single gene product, with each epitope separated by spacer residues to enhance appropriate epitope processing, was designed. Immunogenicity testing in mice demonstrated the induction of multiple CTL and HTL responses. Furthermore, as a complementary approach, mass spectrometry allowed the identification of correctly processed and major histocompatibility complex-presented epitopes from human cells transfected with the DNA plasmid. A heterologous prime-boost immunization with the plasmid DNA and a recombinant MVA gave further enhancement of the immune responses. Thus, a multiepitope therapeutic vaccine candidate capable of stimulating those cellular immune responses thought to be essential for controlling and clearing HBV infection was successfully designed and evaluated in vitro and in HLA transgenic mice.

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Brown, Wendy C., Guy H. Palmer, Harris A. Lewin y Travis C. McGuire. "CD4+ T Lymphocytes from Calves Immunized withAnaplasma marginale Major Surface Protein 1 (MSP1), a Heteromeric Complex of MSP1a and MSP1b, Preferentially Recognize the MSP1a Carboxyl Terminus That Is Conserved among Strains". Infection and Immunity 69, n.º 11 (1 de noviembre de 2001): 6853–62. http://dx.doi.org/10.1128/iai.69.11.6853-6862.2001.

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ABSTRACT Native major surface protein 1 (MSP1) of the ehrlichial pathogenAnaplasma marginale induces protective immunity in calves challenged with homologous and heterologous strains. MSP1 is a heteromeric complex of a single MSP1a protein covalently associated with MSP1b polypeptides, of which at least two (designated MSP1F1 and MSP1F3) in the Florida strain are expressed. Immunization with recombinant MSP1a and MSP1b alone or in combination fails to provide protection. The protective immunity in calves immunized with native MSP1 is associated with the development of opsonizing and neutralizing antibodies, but CD4+ T-lymphocyte responses have not been evaluated. CD4+ T lymphocytes participate in protective immunity to ehrlichial pathogens through production of gamma interferon (IFN-γ), which promotes switching to high-affinity immunoglobulin G (IgG) and activation of phagocytic cells to produce nitric oxide. Thus, an effective vaccine for A. marginaleand related organisms should contain both T- and B-lymphocyte epitopes that induce a strong memory response that can be recalled upon challenge with homologous and heterologous strains. This study was designed to determine the relative contributions of MSP1a and MSP1b proteins, which contain both variant and conserved amino acid sequences, in stimulating memory CD4+ T-lymphocyte responses in calves immunized with native MSP1. Peripheral blood mononuclear cells and CD4+ T-cell lines from MSP1-immunized calves proliferated vigorously in response to the immunizing strain (Florida) and heterologous strains of A. marginale. The conserved MSP1-specific response was preferentially directed to the carboxyl-terminal region of MSP1a, which stimulated high levels of IFN-γ production by CD4+ T cells. In contrast, there was either weak or no recognition of MSP1b proteins. Paradoxically, all calves developed high titers of IgG antibodies to both MSP1a and MSP1b polypeptides. These findings suggest that in calves immunized with MSP1 heteromeric complex, MSP1a-specific T lymphocytes may provide help to MSP1b-specific B lymphocytes. The data provide a basis for determining whether selected MSP1a CD4+ T-lymphocyte epitopes and selected MSP1a and MSP1b B-lymphocyte epitopes presented on the same molecule can stimulate a protective immune response.

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Gao, Yi, Chong Wang y Gary A. Splitter. "Mapping T and B lymphocyte epitopes of bovine herpesvirus-1 glycoprotein B". Journal of General Virology 80, n.º 10 (1 de octubre de 1999): 2699–704. http://dx.doi.org/10.1099/0022-1317-80-10-2699.

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Glycoprotein B (gB) is a major envelope protein of bovine herpesvirus-1 (BHV-1). As a subunit vaccine, the extracellular domain of recombinant gB induces neutralizing antibody and T cell responses that engender protection against virus challenge. Here, lymphocytes from animals of different parentage were analysed for T cell proliferation to the gB extracellular domain for immune recognition. Four truncated overlapping gB gene segments encoding 742 amino acids were expressed from a baculovirus vector to identify antigenic regions. One immunodominant region (amino acids 254–532) was recognized by T cells from immune individuals of different parentage. Serial synthetic peptides spanning this region localized the T cell (amino acids 319–340 and 415–436) and B cell (amino acids 331–352, 475–496 and 487–508) epitopes. Elucidation of gB epitopes indicates the diverse and distinctive recognition by T cells and antibodies of this envelope glycoprotein by cattle, the natural host of BHV-1.

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Li, Zhen, C. Marcela Díaz-Montero, Gustavo Valbuena, Xue-Jie Yu, Juan P. Olano, Hui-Min Feng y David H. Walker. "Identification of CD8 T-Lymphocyte Epitopes in OmpB of Rickettsia conorii". Infection and Immunity 71, n.º 7 (julio de 2003): 3920–26. http://dx.doi.org/10.1128/iai.71.7.3920-3926.2003.

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ABSTRACT The 1.2-kb DNA fragment of the Rickettsia conorii outer membrane protein B gene (OmpB451-846) was subcloned using site-specific PCR primers and expressed as six smaller fragments: OmpB458-652, OmpB595-744, OmpB595-654, OmpB645-692, OmpB689-744, and OmpB739-848. NCTC cells transfected with a mammalian expression vector expressing the fragments OmpB689-744 and OmpB739-848 stimulated immune anti-R. conorii CD8 T lymphocytes, suggesting the presence of CD8 T-lymphocyte-stimulating epitopes on these fragments. In order to further characterize the CD8 T-lymphocyte-stimulatory elements, CD8 T-lymphocyte epitopes on OmpB689-744 and OmpB739-848 were mapped by overlapping synthetic peptides. The ability of these synthetic peptides to stimulate immune CD8 T lymphocytes was determined by gamma interferon (IFN-γ) production and cell proliferation after incubation with simian virus 40-transformed murine vascular endothelial cells in the presence of a 20 μM solution of each synthetic peptide. Five synthetic peptides, SKGVNVDTV (OmpB708-716), ANVGSFVFN (OmpB735-743), IVSGTVGGQ (OmpB749-757), ANSTLQIGG (OmpB789-797), and IVEFVNTGP (OmpB812-820), induced secretion of IFN-γ at significantly higher levels than the controls. Three of these five peptides, SKGVNVDTV (OmpB708-716), ANSTLQIGG (OmpB789-797), and IVEFVNTGP (OmpB812-820), also stimulated the proliferation of immune CD8 T lymphocytes. Significantly higher levels of specific cytotoxic T-lymphocyte killing were observed with the same three synthetic peptides, SKGVNVDTV (OmpB708-716), ANSTLQIGG (OmpB789-797), and IVEFVNTGP (OmpB812-820).

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Westover, Kristi M. y Austin L. Hughes. "Evolution of cytotoxic T-lymphocyte epitopes in hepatitis B virus". Infection, Genetics and Evolution 7, n.º 2 (marzo de 2007): 254–62. http://dx.doi.org/10.1016/j.meegid.2006.10.004.

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Song, Xiaojie, Guanghui Zhao y Meiling Ding. "Antigen Epitope Developed Based on Acinetobacter baumannii MacB Protein Can Provide Partial Immune Protection in Mice". BioMed Research International 2020 (20 de octubre de 2020): 1–11. http://dx.doi.org/10.1155/2020/1975875.

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Acinetobacter baumannii (A. baumannii) is an important opportunistic pathogen widely present in medical environment. Given its complex drug resistance, A. baumannii poses a serious threat to the safety of critically ill patients. Given the limited alternative antibiotics, nonantibiotic-based functional anti-A. baumannii infection proteins must be developed. In this study, we firstly used a series of biological software to predict potential epitopes in the MacB protein sequence and verified them by antibody recognition and lymphocyte proliferation tests. We finally screened out B cell epitope 2, CD8+ T cell epitope 7, and CD4+ T cell epitope 11 and connected them to construct a recombinant antigen epitope (RAE). The determination of IgG in the serum of immunised mice and cytokines in the supernatant of lymphocytes showed that the constructed epitope induced an immune response mediated by Th-1 cells. Finally, the challenge experiment of A. baumannii infection in mice confirmed that the epitope developed based on MacB, especially RAE, provided incomplete immune protection for mice.

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Sominskaya, Irina, Dace Skrastina, Andris Dislers, Denis Vasiljev, Marija Mihailova, Velta Ose, Dzidra Dreilina y Paul Pumpens. "Construction and Immunological Evaluation of Multivalent Hepatitis B Virus (HBV) Core Virus-Like Particles Carrying HBV and HCV Epitopes". Clinical and Vaccine Immunology 17, n.º 6 (21 de abril de 2010): 1027–33. http://dx.doi.org/10.1128/cvi.00468-09.

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ABSTRACT A multivalent vaccine candidate against hepatitis B virus (HBV) and hepatitis C virus (HCV) infections was constructed on the basis of HBV core (HBc) virus-like particles (VLPs) as carriers. Chimeric VLPs that carried a virus-neutralizing HBV pre-S1 epitope corresponding to amino acids (aa) 20 to 47 in the major immunodominant region (MIR) and a highly conserved N-terminal HCV core epitope corresponding to aa 1 to 60 at the C terminus of the truncated HBcΔ protein (N-terminal aa 1 to 144 of full-length HBc) were produced in Escherichia coli cells and examined for their antigenicity and immunogenicity. The presence of two different foreign epitopes within the HBc molecule did not interfere with its VLP-forming ability, with the HBV pre-S1 epitope exposed on the surface and the HCV core epitope buried within the VLPs. After immunization of BALB/c mice, specific T-cell activation by both foreign epitopes and a high-titer antibody response against the pre-S1 epitope were found, whereas an antibody response against the HBc carrier was notably suppressed. Both inserted epitopes also induced a specific cytotoxic-T-lymphocyte (CTL) response, as shown by the gamma interferon (IFN-γ) production profile.

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B., Jesvin Bency y Mary Helen P. A. "Novel epitope based peptides for vaccine against SARS-CoV-2 virus: immunoinformatics with docking approach". International Journal of Research in Medical Sciences 8, n.º 7 (26 de junio de 2020): 2385. http://dx.doi.org/10.18203/2320-6012.ijrms20202875.

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Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative viral strain for the contagious pandemic respiratory illness in humans which is a public health emergency of international concern. There is a desperate need for vaccines and antiviral strategies to combat the rapid spread of SARS-CoV-2 infection.Methods: The present study based on computational methods has identified novel conserved cytotoxic T-lymphocyte epitopes as well as linear and discontinuous B-cell epitopes on the SARS-CoV-2 spike (S) protein. The predicted MHC class I and class II binding peptides were further checked for their antigenic scores, allergenicity, toxicity, digesting enzymes and mutation.Results: A total of fourteen linear B-cell epitopes where GQSKRVDFC displayed the highest antigenicity-score and sixteen highly antigenic 100% conserved T-cell epitopes including the most potential vaccine candidates MHC class-I peptide KIADYNYKL and MHC class-II peptide VVFLHVTYV were identified. Furthermore, the potential peptide QGFSALEPL with high antigenicity score attached to larger number of human leukocyte antigen alleles. Docking analyses of the allele HLA-B*5201 predicted to be immunogenic to several of the selected epitopes revealed that the peptides engaged in strong binding with the HLA-B*5201 allele.Conclusions: Collectively, this research provides novel candidates for epitope-based peptide vaccine design against SARS-CoV-2 infection.

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Isacchini, Giulio, Aleksandra M. Walczak, Thierry Mora y Armita Nourmohammad. "Deep generative selection models of T and B cell receptor repertoires with soNNia". Proceedings of the National Academy of Sciences 118, n.º 14 (1 de abril de 2021): e2023141118. http://dx.doi.org/10.1073/pnas.2023141118.

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Subclasses of lymphocytes carry different functional roles to work together and produce an immune response and lasting immunity. Additionally to these functional roles, T and B cell lymphocytes rely on the diversity of their receptor chains to recognize different pathogens. The lymphocyte subclasses emerge from common ancestors generated with the same diversity of receptors during selection processes. Here, we leverage biophysical models of receptor generation with machine learning models of selection to identify specific sequence features characteristic of functional lymphocyte repertoires and subrepertoires. Specifically, using only repertoire-level sequence information, we classify CD4+ and CD8+ T cells, find correlations between receptor chains arising during selection, and identify T cell subsets that are targets of pathogenic epitopes. We also show examples of when simple linear classifiers do as well as more complex machine learning methods.

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Cho, Seong-Pil, Bumyong Lee y Mi-Kyung Min. "Recombinant polioviruses expressing hepatitis B virus-specific cytotoxic T-lymphocyte epitopes". Vaccine 18, n.º 25 (junio de 2000): 2878–85. http://dx.doi.org/10.1016/s0264-410x(00)00060-8.

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Goulder, Philip J. R., C. Brander, K. Annamalai, N. Mngqundaniso, U. Govender, Y. Tang, S. He et al. "Differential Narrow Focusing of Immunodominant Human Immunodeficiency Virus Gag-Specific Cytotoxic T-Lymphocyte Responses in Infected African and Caucasoid Adults and Children". Journal of Virology 74, n.º 12 (15 de junio de 2000): 5679–90. http://dx.doi.org/10.1128/jvi.74.12.5679-5690.2000.

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ABSTRACT Cytotoxic T-lymphocyte (CTL) activity plays a central role in control of viral replication and in determining outcome in cases of human immunodeficiency virus type 1 (HIV-1) infection. Incorporation of important CTL epitope sequences into candidate vaccines is, therefore, vital. Most CTL studies have focused upon small numbers of adult Caucasoid subjects infected with clade-B virus, whereas the global epidemic is most severe in sub-Saharan African populations and predominantly involves clade-C infection in both adults and children. In this study, sensitive enzyme-linked immunospot (elispot) assays have been utilized to identify the dominant Gag-specific CTL epitopes targeted by adults and children infected with clade-B or -C virus. Cohorts evaluated included 44 B-clade-infected Caucasoid American and African American adults and children and 37 C-clade-infected African adults and children from Durban, South Africa. The results show that 3 out of 46 peptides spanning p17Gag and p24Gagsequences tested contain two-thirds of the dominant Gag-specific epitopes, irrespective of the clade, ethnicity, or age group studied. However, there were distinctive differences between the dominant responses made by Caucasoids and Africans. Dominant responses in Caucasoids were more often within p17Gag peptide residues 16 to 30 (38 versus 12%; P < 0.01), while p24Gag peptide residues 41 to 60 contained the dominant Gag epitope more often in the African subjects tested (39 versus 4%;P < 0.005). Within this 20-mer p24Gag, an epitope presented by both B42 and B81 is defined which represents the dominant Gag response in >30% of the total infected population in Durban. This epitope is closely homologous with dominant HIV-2 and simian immunodeficiency virus Gag-specific CTL epitopes. The fine focusing of dominant CTL responses to these few regions of high immunogenicity is of significance to vaccine design.

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Honeyborne, Isobella, Andrew Prendergast, Florencia Pereyra, Alasdair Leslie, Hayley Crawford, Rebecca Payne, Shabashini Reddy et al. "Control of Human Immunodeficiency Virus Type 1 Is Associated with HLA-B*13 and Targeting of Multiple Gag-Specific CD8+ T-Cell Epitopes". Journal of Virology 81, n.º 7 (24 de enero de 2007): 3667–72. http://dx.doi.org/10.1128/jvi.02689-06.

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ABSTRACT To better understand relationships between CD8+ T-cell specificity and the immune control of human immunodeficiency virus type 1 (HIV-1), we analyzed the role of HLA-B*13, an allele associated with low viremia, in a cohort of 578 C clade-infected individuals in Durban, South Africa. Six novel B*13-restricted cytotoxic T lymphocyte epitopes were defined from analyses of 37 B*13-positive subjects, including three Gag epitopes. These B*13-restricted epitopes contribute to a broad Gag-specific CD8+ response that is associated with the control of viremia. These data are consistent with data from studies of other HLA-class I alleles associated with HIV control that have shown that the targeting of multiple Gag epitopes is associated with relative suppression of viremia.

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O'Connor, David H., Bianca R. Mothe, Jason T. Weinfurter, Sarah Fuenger, William M. Rehrauer, Peicheng Jing, Richard R. Rudersdorf et al. "Major Histocompatibility Complex Class I Alleles Associated with Slow Simian Immunodeficiency Virus Disease Progression Bind Epitopes Recognized by Dominant Acute-Phase Cytotoxic-T-Lymphocyte Responses". Journal of Virology 77, n.º 16 (15 de agosto de 2003): 9029–40. http://dx.doi.org/10.1128/jvi.77.16.9029-9040.2003.

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ABSTRACT Certain major histocompatibility complex class I (MHC-I) alleles are associated with delayed disease progression in individuals infected with human immunodeficiency virus (HIV) and in macaques infected with simian immunodeficiency virus (SIV). However, little is known about the influence of these MHC alleles on acute-phase cellular immune responses. Here we follow 51 animals infected with SIVmac239 and demonstrate a dramatic association between Mamu-A*01 and -B*17 expression and slowed disease progression. We show that the dominant acute-phase cytotoxic T lymphocyte (CTL) responses in animals expressing these alleles are largely directed against two epitopes restricted by Mamu-A*01 and one epitope restricted by Mamu-B*17. One Mamu-A*01-restricted response (Tat28-35SL8) and the Mamu-B*17-restricted response (Nef165-173IW9) typically select for viral escape variants in early SIVmac239 infection. Interestingly, animals expressing Mamu-A*1 and -B*17 have less variation in the Tat28-35SL8 epitope during chronic infection than animals that express only Mamu-A*01. Our results show that MHC-I alleles that are associated with slow progression to AIDS bind epitopes recognized by dominant CTL responses during acute infection and underscore the importance of understanding CTL responses during primary HIV infection.

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Woo, Wai-Ping, Tracy Doan, Karen A. Herd, Hans-Jürgen Netter y Robert W. Tindle. "Hepatitis B Surface Antigen Vector Delivers Protective Cytotoxic T-Lymphocyte Responses to Disease-Relevant Foreign Epitopes". Journal of Virology 80, n.º 8 (15 de abril de 2006): 3975–84. http://dx.doi.org/10.1128/jvi.80.8.3975-3984.2006.

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ABSTRACT Although hepatitis B surface antigen (HBsAg) per se is highly immunogenic, its use as a vector for the delivery of foreign cytotoxic T-lymphocyte (CTL) epitopes has met with little success because of constraints on HBsAg stability and secretion imposed by the insertion of foreign sequence into critical hydrophobic/amphipathic regions. Using a strategy entailing deletion of DNA encoding HBsAg-specific CTL epitopes and replacement with DNA encoding foreign CTL epitopes, we have derived chimeric HBsAg DNA immunogens which elicited effector and memory CTL responses in vitro, and pathogen- and tumor-protective responses in vivo, when the chimeric HBsAg DNAs were used to immunize mice. We further show that HBsAg DNA recombinant for both respiratory syncytial virus and human papillomavirus CTL epitopes elicited simultaneous responses to both pathogens. These data demonstrate the efficacy of HBsAg DNA as a vector for the delivery of disease-relevant protective CTL responses. They also suggest the applicability of the approach of deriving chimeric HBsAg DNA immunogens simultaneously encoding protective CTL epitopes for multiple diseases. The DNAs we tested formed chimeric HBsAg virus-like particles (VLPs). Thus, our results have implications for the development of vaccination strategies using either chimeric HBsAg DNA or VLP vaccines. HBsAg is the globally administered vaccine for hepatitis B virus infection, inviting its usage as a vector for the delivery of immunogens from other diseases.

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Verma, Shilpi, Daniela Weiskopf, Ankan Gupta, Bryan McDonald, Bjoern Peters, Alessandro Sette y Chris A. Benedict. "Cytomegalovirus-Specific CD4 T Cells Are Cytolytic and Mediate Vaccine Protection". Journal of Virology 90, n.º 2 (21 de octubre de 2015): 650–58. http://dx.doi.org/10.1128/jvi.02123-15.

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ABSTRACTCD4 T cells provide protection against cytomegalovirus (CMV) and other persistent viruses, and the ability to quantify and characterize epitope-specific responses is essential to gain a more precise understanding of their effector roles in this regard. Here, we report the first two I-Ad-restricted CD4 T cell responses specific for mouse CMV (MCMV) epitopes and use a major histocompatibility complex class II (MHC-II) tetramer to characterize their phenotypes and functions. We demonstrate that MCMV-specific CD4 T cells can express high levels of granzyme B and kill target cells in an epitope- and organ-specific manner. In addition, CD4 T cell epitope vaccination of immunocompetent mice reduced MCMV replication in the same organs where CD4 cytotoxic T lymphocyte (CTL) activity was observed. Together, our studies show that MCMV epitope-specific CD4 T cells have the potential to mediate antiviral defense by multiple effector mechanismsin vivo.IMPORTANCECD4 T cells mediate immune protection by using their T cell receptors to recognize specific portions of viral proteins, called epitopes, that are presented by major histocompatibility complex class II (MHC-II) molecules on the surfaces of professional antigen-presenting cells (APCs). In this study, we discovered the first two epitopes derived from mouse cytomegalovirus (MCMV) that are recognized by CD4 T cells in BALB/c mice, a mouse strain commonly used to study the pathogenesis of this virus infection. Here, we report the sequences of these epitopes, characterize the CD4 T cells that recognize them to fight off MCMV infection, and show that we can use the epitopes to vaccinate mice and protect against MCMV.

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Bhuiyan, Maruf Ahmed, Syeda Tasnim Quayum, Foysal Ahammad, Rahat Alam, Abdus Samad y Zulkar Nain. "Discovery of potential immune epitopes and peptide vaccine design - a prophylactic strategy against Rift Valley fever virus". F1000Research 9 (18 de agosto de 2020): 999. http://dx.doi.org/10.12688/f1000research.24975.1.

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Background: Rift Valley fever virus (RVFV) is an emerging arbovirus infecting both animals and humans. Any form of direct contact with body fluids, blood or tissue of infected animals is the mode of transmission of this pathogen. Despite being an emerging virus, no proper vaccinations are yet available for the public. Our objective is to compose a multiepitope vaccine utilizing immuno-bioinformatics as a strategy against RVFV. Methods: To identify immunodominant epitopes and design a potent vaccine candidate, we applied a series of immunoinformatic approaches with molecular dynamics and immune response simulation frameworks. Results: A glycoprotein with the highest antigenicity was selected and employed for determining promising epitopes. We selected T cell epitopes based on their immunological potencies and cytokine inducing properties, while B cell epitopes were selected based on their antigenic features. Finally, we selected four cytotoxic T-lymphocyte, two helper T-lymphocyte, and three linear B-lymphocyte epitopes that were arranged into a vaccine construct with appropriate adjuvants and linkers. The chimera protein was modeled, refined, and validated prior to docking against toll-like receptor 4. Docking studies suggest strong binding interactions while dynamics simulation revealed the stable nature of the docked complex. Furthermore, the immune simulation showed robust and prolonged immune responses with rapid antigen clearance. Finally, codon optimization and cloning conducted with Escherichia coli K12 suggests high translation efficiency within the host system. Conclusion: We believe that our designed multiepitope vaccine is a promising prophylactic candidate against RVFV pathogenesis.

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Mir, Gerard Hernandez, Jari Helin, Kari-Pekka Skarp, Richard D. Cummings, Antti Mäkitie, Risto Renkonen y Anne Leppänen. "Glycoforms of human endothelial CD34 that bind L-selectin carry sulfated sialyl Lewis x capped O- and N-glycans". Blood 114, n.º 3 (16 de julio de 2009): 733–41. http://dx.doi.org/10.1182/blood-2009-03-210237.

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Abstract Endothelial sialomucin CD34 functions as an L-selectin ligand mediating lymphocyte extravasation only when properly glycosylated to express a sulfated carbohydrate epitope, 6-sulfo sialyl Lewis x (6-sulfo SLex). It is thought that multivalent 6-sulfo SLex expression promotes high-affinity binding to L-selectin by enhancing avidity. However, the reported low amount of 6-sulfo SLex in total human CD34 is inconsistent with this model and prompted us to re-evaluate CD34 glycosylation. We separated CD34 into 2 glycoforms, the L-selectin–binding and nonbinding glycoforms, L-B-CD34 and L-NB-CD34, respectively, and analyzed released O- and N-glycans from both forms. L-B-CD34 is relatively minor compared with L-NB-CD34 and represented less than 10% of total tonsillar CD34. MECA-79, a mAb to sulfated core-1 O-glycans, bound exclusively to L-B-CD34 and this form contained all sulfated and fucosylated O-glycans. 6-Sulfo SLex epitopes occur on core-2 and extended core-1 O-glycans with approximately 20% of total L-B-CD34 O-glycans expressing 6-sulfo SLex. N-glycans containing potential 6-sulfo SLex epitopes were also present in L-B-CD34, but their removal did not abolish binding to L-selectin. Thus, a minor glycoform of CD34 carries relatively abundant 6-sulfo SLex epitopes on O-glycans that are important for its recognition by L-selectin.

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Brown, Wendy C., Travis C. McGuire, Waithaka Mwangi, Kimberly A. Kegerreis, Henriette Macmillan, Harris A. Lewin y Guy H. Palmer. "Major Histocompatibility Complex Class II DR-Restricted Memory CD4+ T Lymphocytes Recognize Conserved Immunodominant Epitopes of Anaplasma marginale Major Surface Protein 1a". Infection and Immunity 70, n.º 10 (octubre de 2002): 5521–32. http://dx.doi.org/10.1128/iai.70.10.5521-5532.2002.

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ABSTRACT Native major surface protein 1 (MSP1) of Anaplasma marginale, composed of covalently associated MSP1a and MSP1b proteins, stimulates protective immunity in cattle against homologous and heterologous strain challenge. Protective immunity against pathogens in the family Anaplasmataceae involves both CD4+ T cells and neutralizing immunoglobulin G. Thus, an effective vaccine should contain both CD4+ T- and B-lymphocyte epitopes that will elicit strong memory responses upon infection with homologous and heterologous strains. Previous studies demonstrated that the predominant CD4+ T-cell response in MSP1 vaccinates is directed against the MSP1a subunit. The present study was designed to identify conserved CD4+ T-cell epitopes in MSP1a presented by a broadly represented subset of major histocompatibility complex (MHC) class II molecules that would be suitable for inclusion in a recombinant vaccine. Transmembrane protein prediction analysis of MSP1a from the Virginia strain revealed a large hydrophilic domain (HD), extending from amino acids (aa) 1 to 366, and a hydrophobic region extending from aa 367 to 593. The N terminus (aa 1 to 67) includes one 28-aa form A repeat and one 29-aa form B repeat, which each contain an antibody neutralization-sensitive epitope [Q(E)ASTSS]. In MSP1 vaccinates, recombinant MSP1a HD (aa 1 to 366) stimulated recall proliferative responses that were comparable to those against whole MSP1a excluding the repeat region (aa 68 to 593). Peptide mapping determined a minimum of five conserved epitopes in aa 151 to 359 that stimulated CD4+ T cells from cattle expressing DR-DQ haplotypes common in Holstein-Friesian breeds. Peptides representing three epitopes (aa 231 to 266, aa 270 to 279, and aa 290 to 319) were stimulatory for CD4+ T-cell clones and restricted by DR. A DQ-restricted CD4+ T-cell epitope, present in the N-terminal form B repeat (VSSQSDQASTSSQLG), was also mapped using T-cell clones from one vaccinate. Although form B repeat-specific T cells did not recognize the form A repeat peptide (VSSQS_EASTSSQLG), induction of T-cell anergy by this peptide was ruled out. The presence of multiple CD4+ T-cell epitopes in the MSP1a HD, in addition to the neutralization-sensitive epitope, supports the testing of this immunogen for induction of protective immunity against A. marginale challenge.

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Dorrell, Lucy, Tao Dong, Graham S. Ogg, Simon Lister, Steve McAdam, Tim Rostron, Chris Conlon, Andrew J. McMichael y Sarah L. Rowland-Jones. "Distinct Recognition of Non-Clade B Human Immunodeficiency Virus Type 1 Epitopes by Cytotoxic T Lymphocytes Generated from Donors Infected in Africa". Journal of Virology 73, n.º 2 (1 de febrero de 1999): 1708–14. http://dx.doi.org/10.1128/jvi.73.2.1708-1714.1999.

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ABSTRACT We present detailed studies of human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) responses to clade A or C HIV type 1 in three donors infected in East Africa. We define several novel non-clade B CTL epitopes, including some restricted by HLA alleles common in Africans. Although cross-clade CTL recognition of these epitopes does occur, recognition can also be highly clade specific.

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Jones, T. R. y S. L. Hoffman. "Malaria vaccine development." Clinical Microbiology Reviews 7, n.º 3 (julio de 1994): 303–10. http://dx.doi.org/10.1128/cmr.7.3.303.

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The malaria parasite life cycle presents several targets for attack, but these different parts of the life cycle are susceptible to different types of host immune response. For example, the sporozoite is most sensitive to immune antibody, while liver stage parasites can be eliminated by cytotoxic T lymphocytes. Attachment of merozoites to erythrocytes, on the other hand, can be blocked by antibody. Convincing experimental evidence shows that completely protective immunity to malaria can be induced. The challenge now is to design recombinant or synthetic vaccines that induce the right types of immune responses to specific life cycle stages. This requires the identification and characterization of B- and T-lymphocyte epitopes expressed by the parasite or by parasitized host cells. These epitopes must be incorporated into a delivery system that maximizes the interaction between the vaccine epitopes and the host immune system. Many epitopes from several parts of the life cycle are already characterized; development of multivalent vaccines, that is, vaccines which contain immunogens from more than one part of the life cycle, is a promising area for research efforts.

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Li, Jongming, Jos Melenhorst, Nancy Hensel, Katyoun Rezvani, Giuseppe Sconocchia, Yasemin Kilical, Jean Hou, Blanche Curfman, Eugene Major y A. John Barrett. "T-cell responses to peptide fragments of the BK virus T antigen: implications for cross-reactivity of immune response to JC virus". Journal of General Virology 87, n.º 10 (1 de octubre de 2006): 2951–60. http://dx.doi.org/10.1099/vir.0.82094-0.

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Infection with BK virus (BKV) induces both humoral and cellular immunity, but the viral antigens of T-antigen (T-ag) stimulating T-cell responses are largely unknown. To identify BKV-specific T cells in healthy individuals, peripheral blood lymphocytes were cultured with autologous dendritic cells (DCs) loaded with BKV lysate and T cells were screened for intracellular gamma interferon production after stimulation with an overlapping 15mer peptide library of the BKV T-ag. Among many immunogenic peptides identified, four T-ag peptides were identified as candidate major histocompatibility complex class I and II T-cell epitopes, restricted to human leukocyte antigen (HLA)-B*0702, -B*08, -DRB1*0301 and -DRB1*0901. Further, a candidate 9mer peptide, LPLMRKAYL, was confirmed to be restricted to HLA-B*0702 and -B*08. Because the polyomaviruses BKV, JC virus (JCV) and Simian virus 40 (SV40) share extensive sequence similarity in the immunogenic proteins T-ag and VP1, it was hypothesized that, in humans, these proteins contain conserved cytotoxic T-lymphocyte (CTL) target epitopes. Four HLA-restricted conserved epitopes of BKV, JCV and SV40 were identified: HLA-B*07, -B*08 and -DRB1*0901 for T-ag and -A*0201 for VP1. T cells cultured in vitro that were specific for one viral antigen recognized other conserved epitopes. CTLs generated from BKV T-ag and VP1 peptide were cytotoxic to DC targets pulsed with either BKV or JCV. Therefore, infection by one of the two viruses (BKV and JCV) could establish cross-immunity against the other. Although cross-cytotoxicity experiments were not performed with SV40, cross-recognition data from conserved antigen epitopes of polyomaviruses suggest strongly that cross-immunity might also exist among the three viruses.

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Berkhoff, E. G. M., A. C. M. Boon, N. J. Nieuwkoop, R. A. M. Fouchier, K. Sintnicolaas, A. D. M. E. Osterhaus y G. F. Rimmelzwaan. "A Mutation in the HLA-B*2705-Restricted NP383-391 Epitope Affects the Human Influenza A Virus-Specific Cytotoxic T-Lymphocyte Response In Vitro". Journal of Virology 78, n.º 10 (15 de mayo de 2004): 5216–22. http://dx.doi.org/10.1128/jvi.78.10.5216-5222.2004.

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ABSTRACT Viruses can exploit a variety of strategies to evade immune surveillance by cytotoxic T lymphocytes (CTL), including the acquisition of mutations in or adjacent to CTL epitopes. Recently, an amino acid substitution (R384G) in an HLA-B*2705-restricted CTL epitope in the influenza A virus nucleoprotein (nucleoprotein containing residues 383 to 391 [NP383-391]; SRYWAIRTR, where R is the residue that was mutated) was associated with escape from CTL-mediated immunity. The effect of this mutation on the in vitro influenza A virus-specific CTL response was studied. To this end, two influenza A viruses, one with and one without the NP383-391 epitope, were constructed by reverse genetics and designated influenza viruses A/NL/94-384R and A/NL/94-384G, respectively. The absence of the HLA-B*2705-restricted CTL epitope in influenza virus A/NL/94-384G was confirmed by using 51Cr release assays with a T-cell clone specific for the NP383-391 epitope. In addition, peripheral blood mononuclear cells (PBMC) stimulated with influenza virus A/NL/94-384G failed to recognize HLA-B*2705-positive target cells pulsed with the original NP383-391 peptide. The proportion of virus-specific CD8+ gamma interferon (IFN-γ)-positive T cells in in vitro-stimulated PBMC was determined by intracellular IFN-γ staining after restimulation with virus-infected autologous B-lymphoblastoid cell lines and C1R cell lines expressing only HLA-B*2705. The proportion of virus-specific CD8+ T cells was lower in PBMC stimulated in vitro with influenza virus A/NL/94-384G obtained from several HLA-B*2705-positive donors than in PBMC stimulated with influenza virus A/NL/94-384R. This finding indicated that amino acid variations in CTL epitopes can affect the virus-specific CTL response and that the NP383-391 epitope is the most important HLA-B*2705-restricted epitope in the nucleoprotein of influenza A viruses.

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Hulot, Sandrine L., Michael S. Seaman, Pritha Sen, Patrick A. Autissier, Edwin R. Manuel y Norman L. Letvin. "Diverse Cross-Reactive Potential and Vβ Gene Usage of an Epitope-Specific Cytotoxic T-Lymphocyte Population in Monkeys Immunized with Diverse Human Immunodeficiency Virus Type 1 Env Immunogens". Journal of Virology 83, n.º 19 (29 de julio de 2009): 9803–12. http://dx.doi.org/10.1128/jvi.00776-09.

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ABSTRACT An ideal human immunodeficiency virus type 1 (HIV-1) vaccine would elicit potent cellular and humoral immune responses that recognize diverse strains of the virus. In the present study, combined methodologies (flow cytometry, Vβ repertoire analysis, and complementarity-determining region 3 sequencing) were used to determine the clonality of CD8+ T lymphocytes taking part in the recognition of variant epitope peptides elicited in Mamu-A*01-positive rhesus monkeys immunized with vaccines encoding diverse HIV-1 envelopes (Envs). Monkeys immunized with clade B Envs generated CD8+ T lymphocytes that cross-recognized both clade B- and clade C-p41A epitope peptides using a large degree of diversity in Vβ gene usage. However, with two monkeys immunized with clade C Env, one monkey exhibited p41A-specific cytotoxic T-lymphocytes (CTL) with the capacity for cross-recognition of variant epitopes, while the other monkey did not. These studies demonstrate that the cross-reactive potential of variant p41A epitope peptide-specific CTL populations can differ between monkeys that share the same restricting major histocompatibility complex class I molecule and receive the same vaccine immunogens.

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Soltan, Mohamed A., Nada Elbassiouny, Helmy Gamal, Eslam B. Elkaeed, Refaat A. Eid, Muhammad Alaa Eldeen y Ahmed A. Al-Karmalawy. "In Silico Prediction of a Multitope Vaccine against Moraxella catarrhalis: Reverse Vaccinology and Immunoinformatics". Vaccines 9, n.º 6 (18 de junio de 2021): 669. http://dx.doi.org/10.3390/vaccines9060669.

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Moraxella catarrhalis (M. catarrhalis) is a Gram-negative bacterium that can cause serious respiratory tract infections and middle ear infections in children and adults. M. catarrhalis has demonstrated an increasing rate of antibiotic resistance in the last few years, thus development of an effective vaccine is a major health priority. We report here a novel designed multitope vaccine based on the mapped epitopes of the vaccine candidates filtered out of the whole proteome of M. catarrhalis. After analysis of 1615 proteins using a reverse vaccinology approach, only two proteins (outer membrane protein assembly factor BamA and LPS assembly protein LptD) were nominated as potential vaccine candidates. These proteins were found to be essential, outer membrane, virulent and non-human homologs with appropriate molecular weight and high antigenicity score. For each protein, cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL) and B cell lymphocyte (BCL) epitopes were predicted and confirmed to be highly antigenic and cover conserved regions of the proteins. The mapped epitopes constituted the base of the designed multitope vaccine where suitable linkers were added to conjugate them. Additionally, beta defensin adjuvant and pan-HLA DR-binding epitope (PADRE) peptide were also incorporated into the construct to improve the stimulated immune response. The constructed multitope vaccine was analyzed for its physicochemical, structural and immunological characteristics and it was found to be antigenic, soluble, stable, non-allergenic and have a high affinity to its target receptor. Although the in silico analysis of the current study revealed that the designed multitope vaccine has the ability to trigger a specific immune response against M. catarrhalis, additional translational research is required to confirm the effectiveness of the designed vaccine.

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Altfeld, Marcus, Todd M. Allen, Elizabeth T. Kalife, Nicole Frahm, Marylyn M. Addo, Bianca R. Mothe, Almas Rathod et al. "The Majority of Currently Circulating Human Immunodeficiency Virus Type 1 Clade B Viruses Fail To Prime Cytotoxic T-Lymphocyte Responses against an Otherwise Immunodominant HLA-A2-Restricted Epitope: Implications for Vaccine Design". Journal of Virology 79, n.º 8 (15 de abril de 2005): 5000–5005. http://dx.doi.org/10.1128/jvi.79.8.5000-5005.2005.

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) mutates to escape immune selection pressure, but there is little evidence of selection mediated through HLA-A2, the dominant class I allele in persons infected with clade B virus. Moreover, HLA-A2-restricted responses are largely absent in the acute phase of infection as the viral load is being reduced, suggesting that circulating viruses may lack immunodominant epitopes targeted through HLA-A2. Here we demonstrate an A2-restricted epitope within Vpr (Vpr59-67) that is targeted by acute-phase HIV-1-specific CD8+ T cells, but only in a subset of persons expressing HLA-A2. Individuals in the acute stage of infection with viruses containing the most common current sequence within this epitope (consensus sequence) were unable to mount epitope-specific T-cell responses, whereas subjects infected with the less frequent I60L variant all developed these responses. The I60L variant epitope was a stronger binder to HLA-A2 and was recognized by epitope-specific T cells at lower peptide concentrations than the consensus sequence epitope. These data demonstrate that HLA-A2 is capable of contributing to the acute-phase cytotoxic T-lymphocyte response in infected subjects, but that most currently circulating viruses lack a dominant immunogenic epitope presented by this allele, and suggest that immunodominant epitopes restricted by common HLA alleles may be lost as the epidemic matures.

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Srivastava, Sukrit, Sonia Verma, Mohit Kamthania, Rupinder Kaur, Ruchi Kiran Badyal, Ajay Kumar Saxena, Ho-Joon Shin, Michael Kolbe y Kailash C. Pandey. "Structural Basis for Designing Multiepitope Vaccines Against COVID-19 Infection: In Silico Vaccine Design and Validation". JMIR Bioinformatics and Biotechnology 1, n.º 1 (19 de junio de 2020): e19371. http://dx.doi.org/10.2196/19371.

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Background The novel coronavirus disease (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to the ongoing 2019-2020 pandemic. SARS-CoV-2 is a positive-sense single-stranded RNA coronavirus. Effective countermeasures against SARS-CoV-2 infection require the design and development of specific and effective vaccine candidates. Objective To address the urgent need for a SARS-CoV-2 vaccine, in the present study, we designed and validated one cytotoxic T lymphocyte (CTL) and one helper T lymphocyte (HTL) multi-epitope vaccine (MEV) against SARS-CoV-2 using various in silico methods. Methods Both designed MEVs are composed of CTL and HTL epitopes screened from 11 structural and nonstructural proteins of the SARS-CoV-2 proteome. Both MEVs also carry potential B-cell linear and discontinuous epitopes as well as interferon gamma–inducing epitopes. To enhance the immune response of our vaccine design, truncated (residues 10-153) Onchocerca volvulus activation-associated secreted protein-1 was used as an adjuvant at the N termini of both MEVs. The tertiary models for both the designed MEVs were generated, refined, and further analyzed for stable molecular interaction with toll-like receptor 3. Codon-biased complementary DNA (cDNA) was generated for both MEVs and analyzed in silico for high level expression in a mammalian (human) host cell line. Results In the present study, we screened and shortlisted 38 CTL, 33 HTL, and 12 B cell epitopes from the 11 protein sequences of the SARS-CoV-2 proteome. Moreover, the molecular interactions of the screened epitopes with their respective human leukocyte antigen allele binders and the transporter associated with antigen processing (TAP) complex were positively validated. The shortlisted screened epitopes were utilized to design two novel MEVs against SARS-CoV-2. Further molecular models of both MEVs were prepared, and their stable molecular interactions with toll-like receptor 3 were positively validated. The codon-optimized cDNAs of both MEVs were also positively analyzed for high levels of overexpression in a human cell line. Conclusions The present study is highly significant in terms of the molecular design of prospective CTL and HTL vaccines against SARS-CoV-2 infection with potential to elicit cellular and humoral immune responses. The epitopes of the designed MEVs are predicted to cover the large human population worldwide (96.10%). Hence, both designed MEVs could be tried in vivo as potential vaccine candidates against SARS-CoV-2.

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Bailey, Justin R., Thomas M. Williams, Robert F. Siliciano y Joel N. Blankson. "Maintenance of viral suppression in HIV-1–infected HLA-B*57+ elite suppressors despite CTL escape mutations". Journal of Experimental Medicine 203, n.º 5 (8 de mayo de 2006): 1357–69. http://dx.doi.org/10.1084/jem.20052319.

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Rare human immunodeficiency virus 1–infected individuals, termed elite suppressors (ES), maintain plasma virus levels of <50 copies/ml and normal CD4 counts without therapy. The major histocompatibility complex class I allele group human histocompatibility leukocyte antigen (HLA)-B*57 is overrepresented in this population. Mutations in HLA-B*57–restricted epitopes have been observed in ES, but their significance has remained unclear. Here we investigate the extent and impact of cytotoxic T lymphocyte (CTL) escape mutations in HLA-B*57+ ES. We provide the first direct evidence that most ES experience chronic low level viremia. Sequencing revealed a striking discordance between the genotypes of plasma virus and archived provirus in resting CD4+ T cells. Mutations in HLA-B*57–restricted Gag epitopes were present in all viruses from plasma but were rare in proviruses, suggesting powerful selective pressure acting at these epitopes. Surprisingly, strong CD8+ T cell interferon-γ responses were detected against some mutant epitopes found in plasma virus, suggesting the development of de novo responses to viral variants. In some individuals, relative CD8+ T cell interleukin-2 responses showed better correlation with the selection observed in vivo. Thus, analysis of low level viremia reveals an unexpectedly high level of CTL escape mutations reflecting selective pressure acting at HLA-B*57–restricted epitopes in ES. Continued viral suppression probably reflects CTL responses against unmutated epitopes and residual or de novo responses against epitopes with escape mutations.

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Norimine, Junzo, Carlos E. Suarez, Terry F. McElwain, Monica Florin-Christensen y Wendy C. Brown. "Immunodominant Epitopes in Babesia bovis Rhoptry-Associated Protein 1 That Elicit Memory CD4+-T-Lymphocyte Responses in B. bovis-Immune Individuals Are Located in the Amino-Terminal Domain". Infection and Immunity 70, n.º 4 (abril de 2002): 2039–48. http://dx.doi.org/10.1128/iai.70.4.2039-2048.2002.

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ABSTRACT Babesia bovis rhoptry-associated protein 1 (RAP-1), which confers partial protection against B. bovis challenge, is recognized by antibodies and T lymphocytes from cattle that have recovered from infection and are immune to subsequent challenge. RAP-1 is a 60-kDa protein with an N-terminal (NT) region that contains four cysteine residues conserved among all Babesia RAP-1 family members and a C-terminal (CT) region that contains multiple, degenerate, tandem 23-amino-acid (aa) repeats. To define the location of CD4+-T-cell epitopes for vaccine development using a recombinant protein or minigene construct, a series of truncated recombinant RAP-1 proteins and peptides were tested for stimulation of T-cell lines derived from B. bovis-immune cattle. CD4+-T-cell lines from three B. bovis-immune cattle with different DRB3 haplotypes responded to the NT region of RAP-1, whereas T cells from only one animal responded weakly to the CT region. T-cell lines from the three individuals recognized two to six NT-region peptides spanning aa 134 to 316 and representing at least four dominant epitopes. Using RAP-1-specific CD4+-T-cell clones, two NT-region epitopes, EYLVNKVLYMATMNYKT (aa 187 to 203) and EAPWYKRWIKKFR (aa 295 to 307), and one CT-region repeat epitope, FREAPQATKHFL, which is present twice at aa positions 391 to 402 and 414 to 425, were identified. Several peptides representing degenerate repeats of the agonist CT-region peptide FREAPQATKHFL neither stimulated responses of T-cell clones specific for this peptide nor inhibited responses to the agonist peptide. Upon stimulation with specific antigen, T-cell clones specific for NT or CT epitopes produced gamma interferon. The presence of T-helper-cell epitopes in the NT domain of RAP-1, which is highly conserved among otherwise antigenically different strains of B. bovis, supports the inclusion of this region in vaccine constructs to be tested in cattle.

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Boon, A. C. M., G. de Mutsert, Y. M. F. Graus, R. A. M. Fouchier, K. Sintnicolaas, A. D. M. E. Osterhaus y G. F. Rimmelzwaan. "The Magnitude and Specificity of Influenza A Virus-Specific Cytotoxic T-Lymphocyte Responses in Humans Is Related to HLA-A and -B Phenotype". Journal of Virology 76, n.º 2 (15 de enero de 2002): 582–90. http://dx.doi.org/10.1128/jvi.76.2.582-590.2002.

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ABSTRACT The repertoire of human cytotoxic T-lymphocytes (CTL) in response to influenza A viruses has been shown to be directed towards multiple epitopes, with a dominant response to the HLA-A2-restricted M158–66 epitope. These studies, however, were performed with peripheral blood mononuclear cells (PBMC) of individuals selected randomly with respect to HLA phenotype or selected for the expression of one HLA allele without considering an influence of other HLA molecules. In addition, little information is available on the influence of HLA makeup on the overall CTL response against influenza viruses. Here, the influenza A virus-specific CTL response was investigated in groups of HLA-A and -B identical individuals. Between groups the individuals shared two or three of the four HLA-A and -B alleles. After in vitro stimulation of PBMC with influenza virus, the highest CTL activity was found in HLA-A2+ donors. A similar pattern was observed for the precursor frequency of virus-specific CTL (CTLp) ex vivo, with a higher CTLp frequency in HLA-A2-positive donors than in HLA-A2-negative donors, which were unable to recognize the immunodominant M158–66 epitope. In addition, CTL activity and frequency of CTLp for the individual influenza virus epitopes were determined. The frequency of CTLp specific for the HLA-B8-restricted epitope NP380–388 was threefold lower in HLA-B27-positive donors than in HLA-B27-negative donors. In addition, the frequency of CTLp specific for the HLA-A1-restricted epitope NP44–52 was threefold higher in HLA-A1-, -A2-, -B8-, and -B35-positive donors than in other donors, which was confirmed by measuring the CTL activity in vitro. These findings indicate that the epitope specificity of the CTL response is related to the phenotype of the other HLA molecules. Furthermore, the magnitude of the influenza virus-specific CTL response seems dependent on the HLA-A and -B phenotypes.

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Maness, Nicholas J., Levi J. Yant, Chungwon Chung, John T. Loffredo, Thomas C. Friedrich, Shari M. Piaskowski, Jessica Furlott et al. "Comprehensive Immunological Evaluation Reveals Surprisingly Few Differences between Elite Controller and Progressor Mamu-B*17-Positive Simian Immunodeficiency Virus-Infected Rhesus Macaques". Journal of Virology 82, n.º 11 (2 de abril de 2008): 5245–54. http://dx.doi.org/10.1128/jvi.00292-08.

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ABSTRACT The association between particular major histocompatibility complex class I (MHC-I) alleles and control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication implies that certain CD8+ T-lymphocyte (CD8-TL) responses are better able than others to control viral replication in vivo. However, possession of favorable alleles does not guarantee improved prognosis or viral control. In rhesus macaques, the MHC-I allele Mamu-B*17 is correlated with reduced viremia and is overrepresented in macaques that control SIVmac239, termed elite controllers (ECs). However, there is so far no mechanistic explanation for this phenomenon. Here we show that the chronic-phase Mamu-B*17-restricted repertoire is focused primarily against just five epitopes—VifHW8, EnvFW9, NefIW9, NefMW9, and env ARFcRW9—in both ECs and progressors. Interestingly, Mamu-B*17-restricted CD8-TL do not target epitopes in Gag. CD8-TL escape variation occurred in all targeted Mamu-B*17-restricted epitopes. However, recognition of escape variant peptides was commonly observed in both ECs and progressors. Wild-type sequences in the VifHW8 epitope tended to be conserved in ECs, but there was no evidence that this enhances viral control. In fact, no consistent differences were detected between ECs and progressors in any measured parameter. Our data suggest that the narrowly focused Mamu-B*17-restricted repertoire suppresses virus replication and drives viral evolution. It is, however, insufficient in the majority of individuals that express the “protective” Mamu-B*17 molecule. Most importantly, our data indicate that the important differences between Mamu-B*17-positive ECs and progressors are not readily discernible using standard assays to measure immune responses.

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Maness, Nicholas J., Laura E. Valentine, Gemma E. May, Jason Reed, Shari M. Piaskowski, Taeko Soma, Jessica Furlott et al. "AIDS virus–specific CD8+ T lymphocytes against an immunodominant cryptic epitope select for viral escape". Journal of Experimental Medicine 204, n.º 11 (22 de octubre de 2007): 2505–12. http://dx.doi.org/10.1084/jem.20071261.

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Cryptic major histocompatibility complex class I epitopes have been detected in several pathogens, but their importance in the immune response to AIDS viruses remains unknown. Here, we show that Mamu-B*17+ simian immunodeficiency virus (SIV)mac239-infected rhesus macaques that spontaneously controlled viral replication consistently made strong CD8+ T lymphocyte (CD8-TL) responses against a cryptic epitope, RHLAFKCLW (cRW9). Importantly, cRW9-specific CD8-TL selected for viral variation in vivo and effectively suppressed SIV replication in vitro, suggesting that they might play a key role in the SIV-specific response. The discovery of an immunodominant CD8-TL response in elite controller macaques against a cryptic epitope suggests that the AIDS virus–specific cellular immune response is likely far more complex than is generally assumed.

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Laroche, Yves, Stephane Heymans, Sophie Capaert, Frans De Cock, Eddy Demarsin y Désiré Collen. "Recombinant staphylokinase variants with reduced antigenicity due to elimination of B-lymphocyte epitopes". Blood 96, n.º 4 (15 de agosto de 2000): 1425–32. http://dx.doi.org/10.1182/blood.v96.4.1425.

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Abstract Site directed mutagenesis (350 variants) of recombinant staphylokinase (SakSTAR), a potent fibrin-selective thrombolytic agent, was undertaken in order to reduce its antigenicity while maintaining its potency. Variants with K35A, (ie, Lys[K] in position 35 substituted with Ala[A]), E65D or E65Q, K74R or K74Q, E80A+D82A, K130T, and K135R displayed increased enzymatic activity or reduced binding of human staphylokinase-specific antibodies. Additive mutagenesis identified 8 variants with intact thrombolytic potencies, which absorbed down to less than a third of SakSTAR-specific antibodies. Intra-arterial administration in 61 patients with peripheral arterial occlusion caused no significant allergic reactions. Median neutralizing antibody titers (with 15 to 85 percentiles), expressed as microgram (μg) compound neutralized per milliliter plasma, were 4.4 (0.3 to 49) for the variants, compared with 12 (4 to 100) in 70 patients given wild-type SakSTAR (P = .002 by Mann-Whitney rank sum test). Overt neutralizing antibody induction (more than 5 μg compound neutralized per milliliter plasma) was observed in 57 of 70 patients (81%) given wild-type SakSTAR, but only in 28 of 60 patients (47%) treated with variants (P < .0001 by Fisher exact test). On the basis of this study, the variant SakSTAR (K35A, E65Q, K74R, D82A, S84A, T90A, E99D, T101S, E108A, K109A, K130T, K135R) (code SY155) has been selected for further clinical development.

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Laroche, Yves, Stephane Heymans, Sophie Capaert, Frans De Cock, Eddy Demarsin y Désiré Collen. "Recombinant staphylokinase variants with reduced antigenicity due to elimination of B-lymphocyte epitopes". Blood 96, n.º 4 (15 de agosto de 2000): 1425–32. http://dx.doi.org/10.1182/blood.v96.4.1425.h8001425_1425_1432.

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Site directed mutagenesis (350 variants) of recombinant staphylokinase (SakSTAR), a potent fibrin-selective thrombolytic agent, was undertaken in order to reduce its antigenicity while maintaining its potency. Variants with K35A, (ie, Lys[K] in position 35 substituted with Ala[A]), E65D or E65Q, K74R or K74Q, E80A+D82A, K130T, and K135R displayed increased enzymatic activity or reduced binding of human staphylokinase-specific antibodies. Additive mutagenesis identified 8 variants with intact thrombolytic potencies, which absorbed down to less than a third of SakSTAR-specific antibodies. Intra-arterial administration in 61 patients with peripheral arterial occlusion caused no significant allergic reactions. Median neutralizing antibody titers (with 15 to 85 percentiles), expressed as microgram (μg) compound neutralized per milliliter plasma, were 4.4 (0.3 to 49) for the variants, compared with 12 (4 to 100) in 70 patients given wild-type SakSTAR (P = .002 by Mann-Whitney rank sum test). Overt neutralizing antibody induction (more than 5 μg compound neutralized per milliliter plasma) was observed in 57 of 70 patients (81%) given wild-type SakSTAR, but only in 28 of 60 patients (47%) treated with variants (P < .0001 by Fisher exact test). On the basis of this study, the variant SakSTAR (K35A, E65Q, K74R, D82A, S84A, T90A, E99D, T101S, E108A, K109A, K130T, K135R) (code SY155) has been selected for further clinical development.

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Venter, Marietjie, Michael Rock, Adrian J. Puren, Caroline T. Tiemessen y James E. Crowe. "Respiratory Syncytial Virus Nucleoprotein-Specific Cytotoxic T-Cell Epitopes in a South African Population of Diverse HLA Types Are Conserved in Circulating Field Strains". Journal of Virology 77, n.º 13 (1 de julio de 2003): 7319–29. http://dx.doi.org/10.1128/jvi.77.13.7319-7329.2003.

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ABSTRACT This study identifies memory cytotoxic T lymphocyte (CTL) epitopes to respiratory syncytial virus (RSV) in healthy South African adults and demonstrates the conservation of those epitopes in circulating field strains of RSV in South Africa. Thirty-seven healthy adults from a population with diverse HLA backgrounds were screened by gamma interferon (IFN-γ) enzyme-linked immunospot for memory CTL activity in response to overlapping peptides representing the complete nucleoprotein (N) of RSV. Responses of more than 40 spot-forming cells/million cells were detectable in 21 individuals. The significant responses were further characterized, and 14-mer peptides were identified that induced cytolytic activity. Fine mapping of peptides with the highest cytolytic activity identified an HLA-B*08-restricted RSV-specific CTL epitope. The extended 14-mer peptide containing this epitope also induced lysis in the context of A*02-restricted target cells in some individuals. These HLA types are common in the target population; thus, the epitope is useful for studies of CTL responses to RSV in humans. The epitope was detected in healthy adults, reflecting the response generated in the course of previous natural RSV infection. We obtained a large panel of naturally occurring isolates of RSV to determine whether there was evidence of escape from CTL activity in circulating strains. We found that this epitope and a previously identified B*07-restricted N protein epitope were conserved in RSV field strains representing the diversity of circulating genotypes. This work suggests that escape from CTL activity is not common for this acute respiratory infection.

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Zhang, Xiuli, Annie Issagholian, Eric A. Berg, Jordan B. Fishman, Anthony B. Nesburn y Lbachir BenMohamed. "Th-Cytotoxic T-Lymphocyte Chimeric Epitopes Extended by Nε-Palmitoyl Lysines Induce Herpes Simplex Virus Type 1-Specific Effector CD8+ Tc1 Responses and Protect against Ocular Infection". Journal of Virology 79, n.º 24 (15 de diciembre de 2005): 15289–301. http://dx.doi.org/10.1128/jvi.79.24.15289-15301.2005.

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ABSTRACT Molecularly defined vaccine formulations capable of inducing antiviral CD8+ T-cell-specific immunity in a manner compatible with human delivery are limited. Few molecules achieve this target without the support of an appropriate immunological adjuvant. In this study, we investigate the potential of totally synthetic palmitoyl-tailed helper-cytotoxic-T-lymphocyte chimeric epitopes (Th-CTL chimeric lipopeptides) to induce herpes simplex virus type 1 (HSV-1)-specific CD8+ T-cell responses. As a model antigen, the HSV-1 glycoprotein B (498-505) (gB498-505) CD8+ CTL epitope was synthesized in line with the Pan DR peptide (PADRE), a universal CD4+ Th epitope. The peptide backbone, composed solely of both epitopes, was extended by N-terminal attachment of one (PAM-Th-CTL), two [(PAM)2-Th-CTL], or three [(PAM)3-Th-CTL] palmitoyl lysines and delivered to H2b mice in adjuvant-free saline. Potent HSV-1 gB498-505-specific antiviral CD8+ T-cell effector type 1 responses were induced by each of the palmitoyl-tailed Th-CTL chimeric epitopes, irrespective of the number of lipid moieties. The palmitoyl-tailed Th-CTL chimeric epitopes provoked cell surface expression of major histocompatibility complex and costimulatory molecules and production of interleukin-12 and tumor necrosis factor alpha proinflammatory cytokines by immature dendritic cells. Following ocular HSV-1 challenge, palmitoyl-tailed Th-CTL-immunized mice exhibited a decrease of virus replication in the eye and in the local trigeminal ganglion and reduced herpetic blepharitis and corneal scarring. The rational of the molecularly defined vaccine approach presented in this study may be applied to ocular herpes and other viral infections in humans, providing steps are taken to include appropriate Th and CTL epitopes and lipid groups.

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Chen, Huabiao, Alicja Piechocka-Trocha, Toshiyuki Miura, Mark A. Brockman, Boris D. Julg, Brett M. Baker, Alissa C. Rothchild et al. "Differential Neutralization of Human Immunodeficiency Virus (HIV) Replication in Autologous CD4 T Cells by HIV-Specific Cytotoxic T Lymphocytes". Journal of Virology 83, n.º 7 (21 de enero de 2009): 3138–49. http://dx.doi.org/10.1128/jvi.02073-08.

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ABSTRACT Defining the antiviral efficacy of CD8 T cells is important for immunogen design, and yet most current assays do not measure the ability of responses to neutralize infectious virus. Here we show that human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) clones and cell lines derived from infected persons and targeting diverse epitopes differ by over 1,000-fold in their ability to retard infectious virus replication in autologous CD4 T cells during a 7-day period in vitro, despite comparable activity as assessed by gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay. Cell lines derived from peripheral blood mononuclear cells stimulated in vitro with peptides representing targeted Gag epitopes consistently neutralized HIV better than Env-specific lines from the same person, although ineffective inhibition of virus replication is not a universal characteristic of Env-specific responses at the clonal level. Gag-specific cell lines were of higher avidity than Env-specific lines, although avidity did not correlate with the ability of Gag- or Env-specific lines to contain HIV replication. The greatest inhibition was observed with cell lines restricted by the protective HLA alleles B*27 and B*57, but stimulation with targeted Gag epitopes resulted in greater inhibition than did stimulation with targeted Env epitopes even in non-B*27/B*57 subjects. These results assessing functional virus neutralization by HIV-specific CD8 T cells indicate that there are marked epitope- and allele-specific differences in virus neutralization by in vitro-expanded CD8 T cells, a finding not revealed by standard IFN-γ ELISPOT assay currently in use in vaccine trials, which may be of critical importance in immunogen design and testing of candidate AIDS vaccines.

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Thimme, Robert, Kyong-Mi Chang, Janell Pemberton, Alessandro Sette y Francis V. Chisari. "Degenerate Immunogenicity of an HLA-A2-Restricted Hepatitis B Virus Nucleocapsid Cytotoxic T-Lymphocyte Epitope That Is Also Presented by HLA-B51". Journal of Virology 75, n.º 8 (15 de abril de 2001): 3984–87. http://dx.doi.org/10.1128/jvi.75.8.3984-3987.2001.

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ABSTRACT The recent identification of hepatitis B virus (HBV) epitopes restricted by multiple HLA alleles has greatly expanded the epitope repertoire available for T-cell-mediated therapeutic vaccine development. The HLA-B51-restricted peptide HBc19-27 is particularly interesting because it is located entirely within the HLA-A2-restricted HBc18-27 epitope. Here we show that HLA-B51-restricted cytotoxic T lymphocytes specific for HBc19-27 from a patient with acute HBV infection were also able to lyse HLA-B51-positive target cells pulsed with HBc18-27 and to produce gamma interferon when stimulated by that peptide, implying that HBc18-27 can be presented by HLA-B51 as well as by HLA-A2. These results demonstrate the concept of degenerate immunogenicity across HLA class supertype boundaries in a human viral disease setting. In addition, they could facilitate the development of an epitope-based therapeutic vaccine to terminate chronic HBV infection that could provide a broad and diverse population coverage with a single peptide.

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Evans, David T., Peicheng Jing, Todd M. Allen, David H. O'Connor, Helen Horton, John E. Venham, Marian Piekarczyk et al. "Definition of Five New Simian Immunodeficiency Virus Cytotoxic T-Lymphocyte Epitopes and Their Restricting Major Histocompatibility Complex Class I Molecules: Evidence for an Influence on Disease Progression". Journal of Virology 74, n.º 16 (15 de agosto de 2000): 7400–7410. http://dx.doi.org/10.1128/jvi.74.16.7400-7410.2000.

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ABSTRACT Simian immunodeficiency virus (SIV) infection of the rhesus macaque is currently the best animal model for AIDS vaccine development. One limitation of this model, however, has been the small number of cytotoxic T-lymphocyte (CTL) epitopes and restricting major histocompatibility complex (MHC) class I molecules available for investigating virus-specific CTL responses. To identify new MHC class I-restricted CTL epitopes, we infected five members of a family of MHC-defined rhesus macaques intravenously with SIV. Five new CTL epitopes bound by four different MHC class I molecules were defined. These included two Env epitopes bound by Mamu-A*11 and -B*03 and three Nef epitopes bound by Mamu-B*03, -B*04, and -B*17. All four restricting MHC class I molecules were encoded on only two haplotypes (b or c). Interestingly, resistance to disease progression within this family appeared to be associated with the inheritance of one or both of these MHC class I haplotypes. Two individuals that inherited haplotypes b and cseparately survived for 299 and 511 days, respectively, while another individual that inherited both haplotypes survived for 889 days. In contrast, two MHC class I-identical individuals that did not inherit either haplotype rapidly progressed to disease (survived <80 days). Since all five offspring were identical at their Mamu-DRBloci, MHC class II differences are unlikely to account for their patterns of disease progression. These results double the number of SIV CTL epitopes defined in rhesus macaques and provide evidence that allelic differences at the MHC class I loci may influence rates of disease progression among AIDS virus-infected individuals.

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Nicol, Samantha M., Shereen Sabbah, Kevin F. Brulois, Jae U. Jung, Andrew I. Bell y Andrew D. Hislop. "Primary B Lymphocytes Infected with Kaposi's Sarcoma-Associated Herpesvirus Can Be ExpandedIn Vitroand Are Recognized by LANA-Specific CD4+T Cells". Journal of Virology 90, n.º 8 (27 de enero de 2016): 3849–59. http://dx.doi.org/10.1128/jvi.02377-15.

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ABSTRACTKaposi's sarcoma-associated herpesvirus (KSHV) has tropism for B lymphocytes, in which it establishes latency, and can also cause lymphoproliferative disorders of these cells manifesting as primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). T cell immunity is vital for the control of KSHV infection and disease; however, few models of B lymphocyte infection exist to study immune recognition of such cells. Here, we developed a model of B lymphocyte infection with KSHV in which infected tonsillar B lymphocytes were expanded by providing mitogenic stimuli and then challenged with KSHV-specific CD4+T cells. The infected cells expressed viral proteins found in PELs, namely, LANA and viral IRF3 (vIRF3), albeit at lower levels, with similar patterns of gene expression for the major latency, viral interleukin 6 (vIL-6), and vIRF3 transcripts. Despite low-level expression of open reading frame 50 (ORF50), transcripts for the immune evasion genes K3 and K5 were detected, with some downregulation of cell surface-expressed CD86 and ICAM. The vast majority of infected lymphocytes expressed IgM heavy chains with Igλ light chains, recapitulating the features seen in infected cells in MCD. We assessed the ability of the infected lymphocytes to be targeted by a panel of major histocompatibility complex (MHC) class II-matched CD4+T cells and found that LANA-specific T cells restricted to different epitopes recognized these infected cells. Given that at least some KSHV latent antigens are thought to be poor targets for CD8+T cells, we suggest that CD4+T cells are potentially important effectors for thein vivocontrol of KSHV-infected B lymphocytes.IMPORTANCEKSHV establishes a latent reservoir within B lymphocytes, but few models exist to study KSHV-infected B cells other than the transformed PEL cell lines, which have likely accrued mutations during the transformation process. We developed a model of KSHV-infected primary B lymphocytes that recapitulates features seen in PEL and MCD by gene expression and cell phenotype analysis, allowing the study of T cell recognition of these cells. Challenge of KSHV-infected B cells with CD4+T cells specific for LANA, a protein expressed in all KSHV-infected cells and malignanciesin vivo, showed that these effectors could efficiently recognize such targets. Given that the virus expresses immune evasion genes or uses proteins with intrinsic properties, such as LANA, that minimize epitope recognition by CD8+T cells, CD4+T cell immunity to KSHV may be important for maintaining the virus-host balance.

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Kawashima, Yuka, Nozomi Kuse, Hiroyuki Gatanaga, Takuya Naruto, Mamoru Fujiwara, Sachi Dohki, Tomohiro Akahoshi et al. "Long-Term Control of HIV-1 in Hemophiliacs Carrying Slow-Progressing Allele HLA-B*5101". Journal of Virology 84, n.º 14 (21 de abril de 2010): 7151–60. http://dx.doi.org/10.1128/jvi.00171-10.

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ABSTRACT HLA-B*51 alleles are reported to be associated with slow disease progression to AIDS, but the mechanism underlying this association is still unclear. In the present study, we analyzed the effect of HLA-B*5101 on clinical outcome for Japanese hemophiliacs who had been infected with HIV-1 before 1985 and had been recruited in 1998 for this study. HLA-B*5101+ hemophiliacs exhibited significantly slow progression. The analysis of HLA-B*5101-restricted HIV-1-specific cytotoxic T-lymphocyte (CTL) responses to 4 HLA-B*-restricted epitopes in 10 antiretroviral-therapy (ART)-free HLA-B*5101+ hemophiliacs showed that the frequency of Pol283-8-specific CD8+ T cells was inversely correlated with the viral load, whereas the frequencies of CD8+ T cells specific for 3 other epitopes were positively correlated with the viral load. The HLA-B*5101+ hemophiliacs whose HIV-1 replication had been controlled for approximately 25 years had HIV-1 possessing the wild-type Pol283-8 sequence or the Pol283-8V mutant, which does not critically affect T-cell recognition, whereas other HLA-B*5101+ hemophiliacs had HIV-1 with escape mutations in this epitope. The results suggest that the control of HIV-1 over approximately 25 years in HLA-B*5101-positive hemophiliacs is associated with a Pol283-8-specific CD8+ T-cell response and that lack of control of HIV-1 is associated with the appearance of Pol283-8-specific escape mutants.

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Rehermann, B., P. Fowler, J. Sidney, J. Person, A. Redeker, M. Brown, B. Moss, A. Sette y F. V. Chisari. "The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis." Journal of Experimental Medicine 181, n.º 3 (1 de marzo de 1995): 1047–58. http://dx.doi.org/10.1084/jem.181.3.1047.

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Cytotoxic T lymphocytes (CTL) are thought to contribute to viral clearance and liver cell injury during hepatitis B virus (HBV) infection. Using a strategy involving the in vitro stimulation of peripheral blood mononuclear cells (PBMC) with HBV-derived synthetic peptides containing HLA-A2.1, -A31, and -Aw68 binding motifs, we have previously described CTL responses to several epitopes within the HBV nucleocapsid and envelope antigens in patients with acute hepatitis. In this study we define six HLA-A2-restricted CTL epitopes located in the highly conserved reverse transcriptase and RNase H domains of the viral polymerase protein, and we show that the CTL response to polymerase is polyclonal, multispecific, and mediated by CD8+ T cells in patients with acute viral hepatitis, but that it is not detectable in patients with chronic HBV infection or uninfected healthy blood donors. Importantly, the peptide-activated CTL recognize target cells that express endogenously synthesized polymerase protein, suggesting that these peptides represent naturally processed viral epitopes. DNA sequence analysis of the viruses in patients who did not respond to peptide stimulation indicated that CTL nonresponsiveness was not due to infection by viral variants that differed in sequences from the synthetic peptides. CTL specific for one of the epitopes were unable to recognize several naturally occurring viral variants, except at high peptide concentration, underlining the HBV subtype specificity of this response. Furthermore, CTL responses against polymerase, core, and envelope epitopes were detectable for more than a year after complete clinical recovery and seroconversion, reflecting either the persistence of trace amounts of virus or the presence of long lived memory CTL in the absence of viral antigen. Finally, we demonstrated that wild type viral DNA and RNA can persist indefinitely, in trace quantities, in the serum and PBMC after complete clinical and serological recovery, despite a concomitant, vigorous, and sustained polyclonal CTL response. Since viral persistence is not due to escape from CTL recognition under these conditions, the data suggest that HBV may retreat into immunologically privileged sites from which it can seed the circulation and reach CTL-inaccessible tissues, thereby maintaining the CTL response in apparently cured individuals and, perhaps, prolonging the liver disease in patients with chronic hepatitis.

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Kondo, Eisei, Yoshiki Akatsuka, Kiyotaka Kuzushima, Kunio Tsujimura, Shoji Asakura, Kohei Tajima, Yoshitoyo Kagami et al. "Identification of novel CTL epitopes of CMV-pp65 presented by a variety of HLA alleles". Blood 103, n.º 2 (15 de enero de 2004): 630–38. http://dx.doi.org/10.1182/blood-2003-03-0824.

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Abstract Cytomegalovirus (CMV)–specific T-cell immunity plays an important role in protection from CMV disease in immunocompromised patients. Identification of cytotoxic T-lymphocyte (CTL) epitopes is essential for monitoring T-cell immunity and also for immunotherapy. In this and previous studies, CMV-pp65–specific CTL lines were successfully generated from all of 11 CMV-seropositive healthy donors, using pp65-transduced CD40-activated B (CD40-B) cells as antigen-presenting cells. By use of enzyme-linked immunospot (ELISPOT) assays, individual CTL epitopes could be mapped with truncated forms of the pp65 gene. For human leukocyte antigen (HLA) alleles with a known binding motif, CTL epitopes within the defined regions were predicted by computer algorithm. For HLA alleles without a known binding motif (HLA-Cw*0801, -Cw*1202, and -Cw*1502), the epitopes were alternatively identified by step-by-step truncations of the pp65 gene. Through this study, a total of 14 novel CTL epitopes of CMV-pp65 were identified. Interestingly, 3 peptides were found to be presented by 2 different HLA class I alleles or subtypes. Moreover, use of CD40-B cells pulsed with a mixture of synthetic peptides led to generation of pp65-specific CTL lines from some of seronegative donors. The study thus demonstrated an efficient strategy for identifying CTL epitopes presented by a variety of HLA alleles.

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Tellam, Judy, Geoff Connolly, Katherine J. Green, John J. Miles, Denis J. Moss, Scott R. Burrows y Rajiv Khanna. "Endogenous Presentation of CD8+ T Cell Epitopes from Epstein-Barr Virus–encoded Nuclear Antigen 1". Journal of Experimental Medicine 199, n.º 10 (17 de mayo de 2004): 1421–31. http://dx.doi.org/10.1084/jem.20040191.

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Epstein-Barr virus (EBV)–encoded nuclear antigen (EBNA)1 is thought to escape cytotoxic T lymphocyte (CTL) recognition through either self-inhibition of synthesis or by blockade of proteasomal degradation by the glycine-alanine repeat (GAr) domain. Here we show that EBNA1 has a remarkably varied cell type–dependent stability. However, these different degradation rates do not correspond to the level of major histocompatibility complex class I–restricted presentation of EBNA1 epitopes. In spite of the highly stable expression of EBNA1 in B cells, CTL epitopes derived from this protein are efficiently processed and presented to CD8+ T cells. Furthermore, we show that EBV-infected B cells can readily activate EBNA1-specific memory T cell responses from healthy virus carriers. Functional assays revealed that processing of these EBNA1 epitopes is proteasome and transporter associated with antigen processing dependent. We also show that the endogenous presentation of these epitopes is dependent on the newly synthesized protein rather than the long-lived stable EBNA1. Based on these observations, we propose that defective ribosomal products, not the full-length antigen, are the primary source of endogenously processed CD8+ T cell epitopes from EBNA1.

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Ober, Bertram T., Artur Summerfield, Christina Mattlinger, Karl-Heinz Wiesmüller, Günther Jung, Eberhard Pfaff, Armin Saalmüller y Hanns-Joachim Rziha. "Vaccine-Induced, Pseudorabies Virus-Specific, Extrathymic CD4+CD8+ Memory T-Helper Cells in Swine". Journal of Virology 72, n.º 6 (1 de junio de 1998): 4866–73. http://dx.doi.org/10.1128/jvi.72.6.4866-4873.1998.

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ABSTRACT Pseudorabies virus (PRV; suid herpesvirus 1) infection causes heavy economic losses in the pig industry. Therefore, vaccination with live attenuated viruses is practiced in many countries. This vaccination was demonstrated to induce extrathymic virus-specific memory CD4+CD8+ T lymphocytes. Due to their major histocompatibility complex (MHC) class II-restricted proliferation, it is generally believed that these T lymphocytes function as memory T-helper cells. To directly prove this hypothesis, 15-amino-acid, overlapping peptides of the viral glycoprotein gC were used for screening in proliferation assays with peripheral blood mononuclear cells of vaccinated d/d haplotype inbred pigs. In these experiments, two naturally processed T-cell epitopes (T1 and T2) which are MHC class II restricted were identified. It was shown that extrathymic CD4+CD8+ T cells are the T-lymphocyte subpopulation that responds to epitope T2. In addition, we were able to show that cytokine secretion can be induced in these T cells through recall with inactivated PRV and demonstrated that activated PRV-primed CD4+CD8+ T cells are able to induce PRV-specific immunoglobulin synthesis by PRV-primed, resting B cells. Taken together, these results demonstrate that the glycoprotein gC takes part in the priming of humoral anti-PRV memory responses. The experiments identified the first T-cell epitopes so far known to induce the generation of virus-specific CD4+CD8+ memory T lymphocytes and showed that CD4+CD8+ T cells are memory T-helper cells. Therefore, this study describes the generation of virus-specific CD4+CD8+ T cells, which is observed during vaccination, as a part of the potent humoral anti-PRV memory response induced by the vaccine.

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Catera, Rosa, Katerina Hatzi, Charles C. Chu, Maxime Herve’, Eric Meffre, Manlio Ferrarini, David Graham Oscier et al. "Polyreactive Monoclonal Antibodies Synthesized by Some B-CLL Cells Recognize Specific Antigens on Viable and Apoptotic T Cells." Blood 108, n.º 11 (16 de noviembre de 2006): 2813. http://dx.doi.org/10.1182/blood.v108.11.2813.2813.

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Abstract B-cell chronic lymphocytic leukemia (CLL) is a disease characterized by uncontrolled clonal expansion of a CD5+/CD19+ B cell. Clones from different patients often express receptors/mAbs with remarkably similar VHDJH rearrangements, suggesting that the same antigen(s) or epitope(s) led to the initial clonal expansion. Although the specific antigens and epitopes remain to be identified, recent data indicate that B-CLL mAbs often bind autoantigens. In certain systemic autoimmune diseases, autoantibodies can react with cell surface molecules of viable lymphocytes (anti-lymphocyte mAbs) and with intracellular molecules of apoptotic cells that are transported to the cell membrane and function as autoantigens. Therefore, we expressed recombinant antibodies from B-CLL cells as IgG1 mAbs and tested them by flow cytometry for immunoreactivity with surface molecules on irradiated (apoptotic) and non-irradiated Jurkat cells, a human T-cell line. We chose to use T cells as our target for analysis to avoid difficulties that might arise from binding to FcgRIIb on B lymphocytes. Initial screening indicated that 5 of 25 mAbs showed intense binding. Antibodies from CLL Nos. 141 and DO8 bound to live but not apoptotic cells; in contrast, CLL Nos. 014, 114, and DO13 bound to apoptotic but not live cells. These five antibodies express unmutated VH genes. CLL 141 and DO8 express VH4-34. CLL 014 expresses VH1-69, CLL 114 VH4-39 and DO13 VH1-02. Other antibodies expressing VH1-69 in its unmutated form also bound Jurkat cells, albeit weaker than CLL 014, whereas mAbs expressing different unmutated genes from the VH1 family did not react. Among the mAbs expressing VH1-02 that were tested, only DO13 showed reactivity. This indicates that the VH1-02 gene was not solely responsible for the observed binding, and that DJ and/or VLJL segments were also involved. Remarkably, none of the tested mAbs belonging to VH3 family recognize antigens on Jurkat cells; all of these VH3 mAbs were mutated. Only CLL 114 belongs to a previously identified stereotypic set. Of interest, although CLL 014 and 141 are polyreactive, binding ssDNA, dsDNA, insulin, LPS, and HEp-2 cell lysates, their reactivities with surface antigens were specific in that CLL 141 bound only live cells and CLL 014 reacted solely with apoptotic cells. Our results indicate that, despite their inherent polyreactivity, certain B-CLL mAb bind specifically to antigenic epitopes on the surface of live as well as apoptotic Jurkat cells. The identity of these autoantigens is currently being investigated. These data highlight the importance of autoreactivity in the promotion and evolution of B-CLL.

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de Haan, Lolke, Arron R. Hearn, A. Jennifer Rivett y Timothy R. Hirst. "Enhanced Delivery of Exogenous Peptides into the Class I Antigen Processing and Presentation Pathway". Infection and Immunity 70, n.º 6 (junio de 2002): 3249–58. http://dx.doi.org/10.1128/iai.70.6.3249-3258.2002.

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ABSTRACT Current immunization strategies, using peptide or protein antigens, generally fail to elicit cytotoxic-T-lymphocyte responses, since these antigens are unable to access intracellular compartments where loading of major histocompatibility complex class I (MHC-I) molecules occurs. In an attempt to circumvent this, we investigated whether the GM1 receptor-binding B subunit of Escherichia coli heat-labile toxin (EtxB) could be used to deliver class I epitopes. When a class I epitope was conjugated to EtxB, it was delivered into the MHC-I presentation pathway in a GM1-binding-dependent fashion and resulted in the appearance of MHC-I-epitope complexes at the cell surface. Importantly, we show that the efficiency of EtxB-mediated epitope delivery could be strikingly enhanced by incorporating, adjacent to the class I epitope, a 10-amino-acid segment from the C terminus of the DNA polymerase (Pol) of herpes simplex virus. The replacement of this 10-amino-acid segment by a heterologous sequence or the introduction of specific amino acid substitutions within this segment either abolished or markedly reduced the efficiency of class I epitope delivery. If the epitope was extended at its C terminus, EtxB-mediated delivery into the class I presentation pathway was found to be completely dependent on proteasome activity. Thus, by combining the GM1-targeting function of EtxB with the 10-amino-acid Pol segment, highly efficient delivery of exogenous epitopes into the endogenous pathway of class I antigen processing and presentation can be achieved.

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Sundaramurthi, Jagadish Chandrabose, V. D. Ramanathan y Luke Elizabeth Hanna. "HLA-B*27:05-Specific Cytotoxic T Lymphocyte Epitopes in Indian HIV Type 1C". AIDS Research and Human Retroviruses 29, n.º 1 (enero de 2013): 47–53. http://dx.doi.org/10.1089/aid.2011.0374.

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Yazdi, M., M. Kolahi, A. M. Foroghmand y M. R. Tabandeh. "In silico assessment of plant L-asparaginase and estimating its allergenicity in comparison to bacteria asparaginase". Pediatric Hematology/Oncology and Immunopathology 19, n.º 1 (28 de marzo de 2020): 35–46. http://dx.doi.org/10.24287/1726-1708-2020-19-1-35-46.

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L-asparaginase is widely distributed among microorganisms, animals and plants. L-asparaginase has been utilized as a drug in the treatment of lymphoid malignancies and plays a crucial role in asparagine metabolism in plant stress response mechanisms. Multiple sequence alignment of Neighbor–Joining phylogenetic tree was executed utilizing Mega 4.0. Two plants asparaginase were identified whose three dimensional structures compared well with two bacterial samples of L-asparaginase used in humans as a therapeutic drug. Prediction of antigen cites, B-cell epitope identification and prediction of epitopes by use of Cytotoxic T-lymphocyte was performed using various in silico server resources. The survey showed that between the 40 plants, 2 identified items of human, 12 bacteria and 6 algae of asparaginase genes, generally two main branches created that samples of green algae is in the neighborhood of to the bacterial samples. Interestingly the data showed that the two bacterial samples of L-asparaginase used in medicine, when compared to plant asparaginase genes, have less similarity to asparaginase genes of human, while the two human asparaginase genes are located perfectly between the plant groups with their sequence revealing high similarity with plant species. Although there was some allergen epitope found in plant asparaginase, these are different from the allergen epitopes of microbial asparaginase that are used as a drug in humans with no common sequence being found between them. This manuscript provides evidence suggesting the potential utilization of Phaseolus vulgaris asparaginase, which has less epitopes, better predicting tool scores and high similarity, in drug design as an enzymetherapy in leukemia and other cancers.

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