MHC-BOUND, SIV-DERIVED, CTL AND HTL EPITOPES

MHC 结合、SIV 衍生、CTL 和 HTL 表位

• 批准号: 8173061
• 负责人: David I Watkins
• 金额: $ 5.16万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173061
• 关键词: Affinity; Algorithms; Alleles; Animals; Ascaridil; Binding; Binding Sites; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Line; Chronic Phase; Computer Retrieval of Information on Scientific Projects Database; Detection; Epitope Mapping; Epitopes; Flow Cytometry; Frequencies; Funding; Gagging; Gene Frequency; Genotype; Grant; HIV; HIV Seropositivity; HLA-B 2705 antigen; HLA-B27 Antigen; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class I; Human; Immune response; Immunologic Deficiency Syndromes; Immunology; Infection; Institution; MHC Class II Genes; Macaca mulatta; Peptides; Process; Publishing; Reagent; Research; Research Personnel; Resources; SIV; Services; Shivering; Source; T cell response; T-Lymphocyte; Testing; United States National Institutes of Health; Vaccines; Viral; Viremia; Virus Replication; Work; bean; cytotoxic; instrument; interest; macrophage; response; tool; vaccine development; virology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To work on developing a vaccine for HIV, we will identify additional epitopes for cytotoxic and helper T cells and use this information to develop unique reagents for following immune responses. HLA-B27- and -B57-positive HIV-infected humans have long been associated with control of HIV replication, implying that CD8+ T cell responses contribute to control of viral replication. In a similar fashion, fifty percent of Mamu-B*08-positive Indian rhesus macaques control SIVmac239 replication and become elite controllers with chronic phase viremia below 1,000 vRNA copies/ml. Therefore, it is of continuing interest to map epitopes presented by successful vaccinees, as well as the alleles that present them, as a means to more fully understand the immune response to SIV and give SIV researchers more tools and target for vaccine development. In 2008-2009 we defined a motif for Mamu-B*22, which has a frequency of 29%, a fairly high frequency allele. An algorithm has been developed to incorporate this new binding site, predicted peptides have been defined and ordered, and binding studies are underway to determine the peptides which bind with highest affinity. In early 2010, we will test these peptides in SIV infected animals to determine which are actually presented to T cells. All of the cell lines needed for these studies are now in place, and a list of infected animals with this genotype has been developed. We have also defined motifs for Mamu-B*48 (frequency 10%), Mamu-B*52 (frequency 7%) and B*29. We have epitopes defined for Mamu-A*07, and have already published a study featuring this allele. In 2010, we will define motifs for Mamu-B*12, -B*30, -B*47, -B*64 and A*06. In 2009 and 2010, we have started mapping epitopes and alleles present in the successful vaccinees from our study published in June 2009. In this study, 6 of 8 vaccinees continue to control viremia below the level of detection. Finally, we are now starting the process of motif determination for MHC class II alleles. We have defined over 30 SIV-defined MHC class II allele and peptide pairs by looking at CD4+ T cell responses present in elite controllers and successful vaccinees. This study also uses resources from the MHC typing facility and Immunology and Virology Services Unit, Elispot and flow cytometry instruments. PUBLICATIONS: Wilson NA, Keele BF, Reed JS, Piaskowski SM, MacNair CE, Bett AJ, Liang X, Wang F, Thoryk E, Heidecker GJ, Citron MP, Huang L, Lin J, Vitelli S, Ahn CD, Kaizu M, Maness NJ, Reynolds MR, Friedrich TC, Loffredo JT, Rakasz EG, Erickson S, Allison DB, Piatak M Jr, Lifson JD, Shiver JW, Casimiro DR, Shaw GM, Hahn BH, Watkins DI. Vaccine-induced cellular responses control simian immunodeficiency virus replication after heterologous challenge. J Virol. 2009 Jul;83(13):6508-21. Epub 2009 Apr 29. PMID: 19403685 Loffredo JT, Sidney J, Bean AT, Beal DR, Bardet W, Wahl A, Hawkins OE, Piaskowski S, Wilson NA, Hildebrand WH, Watkins DI, Sette A. Two MHC class I molecules associated with elite control of immunodeficiency virus replication, Mamu-B*08 and HLA-B*2705, bind peptides with sequence similarity. J Immunol. 2009 Jun 15;182(12):7763-75. PMID: 19494300 Sacha JB, Giraldo-Vela JP, Buechler MB, Martins MA, Maness NJ, Chung C, Wallace LT, Le¿n EJ, Friedrich TC, Wilson NA, Hiraoka A, Watkins DI. Gag- and Nef-specific CD4+ T cells recognize and inhibit SIV replication in infected macrophages early after infection. Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9791-6. Epub 2009 May 28. PMID: 19478057

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以出现在其他 CRISP 条目中 列出的机构是。 中心，不一定是研究者的机构。 目的：为了开发 HIV 疫苗，我们将确定细胞毒性 T 细胞和辅助 T 细胞的其他表位，并利用这些信息开发用于后续免疫反应的独特试剂。 HLA-B27-和-B57-阳性HIV感染者长期以来一直与HIV复制的控制相关，这意味着CD8+ T细胞反应以类似的方式有助于控制病毒复制，50%的Mamu-B*08-。阳性印度恒河猴控制 SIVmac239 复制，并成为慢性期病毒血症低于 1,000 个 vRNA 拷贝/ml 的精英控制者。成功的疫苗以及代表它们的等位基因，作为更全面地了解对 SIV 的免疫反应的一种手段，并为 SIV 研究人员提供更多的疫苗开发工具和目标。 2008-2009 年，我们定义了 Mamu-B*22 的基序，其频率为 29%，是一个相当高频率的等位基因，已开发出一种算法来合并此新的结合位点，已定义并排序了预测的肽，并且结合研究正在进行中，以确定具有最高亲和力的肽。2010 年初，我们将在 SIV 感染的动物中测试这些肽，以确定哪些肽实际上被呈递给 T 细胞所需的所有细胞系。这些研究现已到位，并已制定了具有该基因型的受感染动物名单。 我们还定义了 Mamu-B*48（频率 10%）、Mamu-B*52（频率 7%）和 B*29 的基序。我们定义了 Mamu-A*07 的表位，并且已经发表了一项研究。 2010 年，我们将为 Mamu-B*12、-B*30、-B*47、-B*64 和 A*06 定义基序。 2009 年和 2010 年，我们开始绘制 2009 年 6 月发表的研究中成功疫苗中存在的表位和等位基因图谱。在这项研究中，8 种疫苗中有 6 种继续将病毒血症控制在检测水平以下。 最后，我们现在开始确定 MHC II 类等位基因的基序过程。通过观察精英控制者和成功疫苗接种者中存在的 CD4+ T 细胞反应，我们已经定义了 30 多个 SIV 定义的 MHC II 类等位基因和肽对。 这项研究还使用了 MHC 分型设施、免疫学和病毒学服务单位、Elispot 和流式细胞术仪器的资源。 出版物： Wilson NA、Keele BF、Reed JS、Piaskowski SM、MacNair CE、Bett AJ、Liang X、Wang F、Thoryk E、Heidecker GJ、Citron MP、Huang L、Lin J、Vitelli S、Ahn CD、Kaizu M、Maness NJ , 雷诺兹 MR, 弗里德里希 TC, 洛弗雷多 JT, 拉卡斯 EG, 埃里克森 S, 艾里森 DB, 皮亚塔克 M Jr, Lifson JD、Shiver JW、Casimiro DR、Shaw GM、Hahn BH、Watkins DI。异源攻击后疫苗诱导的细胞反应控制猿猴免疫缺陷病毒复制。2009 年 7 月；83(13)：6508-21。 29.PMID：19403685 Loffredo JT、Sidney J、Bean AT、Beal DR、Bardet W、Wahl A、Hawkins OE、Piaskowski S、Wilson NA、Hildebrand WH、Watkins DI、Sette A。两种与免疫缺陷病毒复制的精英控制相关的 MHC I 类分子， Mamu-B*08 和 HLA-B*2705 结合具有序列相似性的肽，2009 年 6 月。 15；182(12)：7763-75。 Sacha JB、Giraldo-Vela JP、Buechler MB、Martins MA、Maness NJ、Chung C、Wallace LT、Le¿ n EJ、Friedrich TC、Wilson NA、Hiraoka A、Watkins DI。Gag 和 Nef 特异性 CD4+ T 细胞在感染后早期识别并抑制受感染巨噬细胞中的 SIV 复制。2009 年 6 月 16 日；106(24) ）：9791-6。Epub 2009 年 5 月 28 日。PMID：19478057