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

MHC 结合、SIV 衍生、CTL 和 HTL 表位

• 批准号: 7958726
• 负责人: David I Watkins
• 金额: $ 19.66万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958726
• 关键词: Animals; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Chronic Phase; Computer Retrieval of Information on Scientific Projects Database; Epitopes; Funding; Gagging; Grant; HIV; HIV Seropositivity; HLA-B 2705 antigen; HLA-B27 Antigen; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class I; Human; Immune response; Immunogenetics; Immunologic Deficiency Syndromes; Institution; Knowledge; Macaca; Macaca mulatta; Modeling; Nature; Peptides; Play; Positioning Attribute; Primates; Reagent; Research; Research Personnel; Resources; Role; Services; Source; T-Lymphocyte; United States National Institutes of Health; Viral; Viremia; Virus Replication; Wisconsin; Work; cytotoxic; novel; response; 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. Interestingly, Mamu-B*08-restricted SIV-derived epitopes appeared to match the peptide binding profile for HLA-B*2705 in humans. We, therefore, defined a detailed peptide-binding motif for Mamu-B*08 and investigated binding similarities between the macaque and human MHC class I molecules. Analysis of a panel of almost 900 peptides revealed that despite substantial sequence differences between Mamu-B*08 and HLA-B*2705, the peptide-binding repertoires of these two MHC class I molecules share a remarkable degree of overlap. Detailed knowledge of the Mamu-B*08 peptide-binding motif enabled us to identify six additional novel Mamu-B*08-restricted SIV-specific CD8+ T cell immune responses directed against epitopes in Gag, Vpr, and Env. All 13 Mamu-B*08-restricted epitopes contain an R at the position 2 primary anchor, and 10 also possess either R or K at the N-terminus. Such dibasic peptides are less prone to cellular degradation. This work highlights the relevance of the Mamu-B*08-positive SIV-infected Indian rhesus macaque as a model to examine elite control of immunodeficiency virus replication. The remarkable similarity of the peptide-binding motifs and repertoires for Mamu-B*08 and HLA-B*2705 suggests that the nature of the peptide bound by the MHC class I molecule may play an important role in control of immunodeficiency virus replication. This research used WNPRC Immunogenetics & Virology Services and Animal Services.

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。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它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 细胞反应有助于控制病毒复制。 以类似的方式，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 vRNA 拷贝/ml 的精英控制者。 有趣的是，Mamu-B*08 限制性 SIV 衍生表位似乎与人类 HLA-B*2705 的肽结合谱相匹配。 因此，我们定义了 Mamu-B*08 的详细肽结合基序，并研究了猕猴和人类 MHC I 类分子之间的结合相似性。 对一组近 900 个肽的分析表明，尽管 Mamu-B*08 和 HLA-B*2705 之间存在显着的序列差异，但这两种 MHC I 类分子的肽结合库具有显着程度的重叠。 对 Mamu-B*08 肽结合基序的详细了解使我们能够鉴定出另外六种新型 Mamu-B*08 限制性 SIV 特异性 CD8+ T 细胞免疫应答，这些免疫应答针对 Gag、Vpr 和 Env 中的表位。 所有 13 个 Mamu-B*08 限制性表位在 2 号主锚定位置均包含 R，另外 10 个表位在 N 末端还包含 R 或 K。 这种二元肽不太容易被细胞降解。 这项工作强调了 Mamu-B*08 阳性 SIV 感染的印度恒河猴作为模型来检查免疫缺陷病毒复制的精英控制的相关性。 Mamu-B*08 和 HLA-B*2705 的肽结合基序和全部成分显着相似，表明 MHC I 类分子结合的肽的性质可能在控制免疫缺陷病毒复制中发挥重要作用。这项研究使用了 WNPRC 免疫遗传学和病毒学服务以及动物服务。