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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 目标：为了开发一种艾滋病毒疫苗，我们将确定其他 细胞毒性T细胞和辅助性T细胞的表位，并利用这些信息开发出独特的 追踪免疫反应的试剂。 进度： 人类白细胞抗原B27和B57阳性的艾滋病毒感染者长期以来一直与 控制HIV复制，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 猕猴控制着SIVmac239复制，成为慢性疾病的精英控制者 相病毒血症低于1,000 vRNA拷贝/毫升。因此，继续关注 成功接种疫苗的人提出的MAP表位以及存在的等位基因 作为一种更全面了解SIV免疫应答的手段，并给予SIV 研究人员为疫苗开发提供了更多的工具和目标。 虽然我们曾希望在疫苗和疫苗中测试MAMU-B*22的多肽 感染了该基因的动物，亲和力出现了延迟 由于MAMU-B*22单体的技术问题而进行的测定研究 由我们的合作者制作。一旦Sette博士的团队完成了这些 2011年，我们将继续绘制这些多肽的图谱。 我们还定义了MAMU-B*48(频率10%)、MAMU-B*52(频率 7%)和B*29。我们已经为MAMU-A*07定义了表位，并且已经 发表了一项以该等位基因为特征的研究。2011年，我们将继续为以下主题定义主题 马木-B*12、-B*30、-B*47、-B*和A*06。 在2009年和2010年，我们开始绘制成功的 我们研究的疫苗接种者于2009年6月发表。在这项研究中，8名疫苗接种者中有6名 继续将病毒血症控制在检测水平以下。此外，在我们新的 在疫苗接种研究中，我们特意纳入了MAMU-A*07和MAMU-B*22 为了便于发展阳性动物的细胞系和作图 这些表位。我们有13个潜在的表位，其中5个已经被确认 其中一些也是在我们接种疫苗的过程中诱发的。新世界里的动物 疫苗接种/挑战研究将于2月份开始挑战，因此到那时 我们将能够跟踪这些疫苗诱导的反应，并确定 在一定程度上，他们能够减少这些动物的病毒血症。我们正在准备一项 描述这些反应的手稿。 最后，我们现在开始确定MHC II类的基序 等位基因。我们已经定义了30多个SIV定义的MHC II类等位基因和多肽对 观察精英控制员和成功接种疫苗的人体内存在的CD4+T细胞反应。 我们已经在新的疫苗/挑战研究中对动物进行了基因分型，并 在疫苗接种期间观察到这些MHC II类限制性反应的发展 相位。我们已经开发了一种MHC II类四聚体，但数量有限 在这项研究中使用。 这项研究还使用了MHC分型设备和病毒学& 免疫学服务单位，ELISPOT和流式细胞仪。 出版物： 吉拉尔多-贝拉JP，比恩AT，鲁德斯多夫R，华莱士LT，洛夫雷多JT，埃里克森P， 威尔逊·纳，沃特金斯探长。猴免疫缺陷病毒特异性CD4+T细胞来源 成功的疫苗接种者瞄准的是SIV恶作剧衣壳。免疫遗传学。2010年 10月；62(10)：701-7。EPub 2010年9月2日。PMID：20812010，PMC3018234。 马丁斯·马，威尔逊·纳，里德·JS，安·CD，Klimentidis YC，艾莉森·DB，沃特金斯 迪。异种猿猴接种后T细胞与疫苗效力的相关性 免疫缺陷病毒挑战。J·维罗尔。2010年5月；84(9)：4352-65。EPub 2010年2月 17.PMID：20164222，PMC2863752。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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. PROGRESS: 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, 50 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. While we had hoped to be testing peptides for Mamu-B*22 in vaccinated and infected animals of that genotype, there has been a delay in the affinity determination studies due to technical issues with the Mamu-B*22 monomers produced by our collaborators. Once Dr. Sette's group has completed these determinations, we will continue to map these peptides in 2011. 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 2011, we will continue to define motifs for Mamu-B*12, -B*30, -B*47, -B*64 and A*06. In 2009 and 2010, we started mapping epitopes and alleles present in the successful vaccinees from our study published in June 2009. In this study, six of eight vaccinees continue to control viremia below the level of detection. In addition, in our new vaccination studies, we have deliberately included Mamu-A*07 and Mamu-B*22 positive animals in order to facilitate the development of cell lines and mapping of these epitopes. We have 13 potential epitopes of which five have been confirmed and some of these were also induced during our vaccination. The animals in the new vaccination/challenge study will be challenged starting in February, so at that time we will be able to follow these vaccine-induced responses and determine to what extent they are able to reduce viremia in these animals. We are preparing a manuscript to describe these responses. 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. We have genotyped the animals in the new vaccine/challenge study and have observed development of these MHC class II-restricted responses during the vaccine phase. We have developed one MHC class II tetramer, but only have limited amounts for use during this study. This study also uses resources from the MHC typing facility and Virology & Immunology Services Unit, Elispot and flow cytometry instruments. PUBLICATIONS: Giraldo-Vela JP, Bean AT, Rudersdorf R, Wallace LT, Loffredo JT, Erickson P, Wilson NA, Watkins DI. Simian immunodeficiency virus-specific CD4+ T cells from successful vaccinees target the SIV Gag capsid. Immunogenetics. 2010 Oct; 62(10):701-7. Epub 2010 Sep 2. PMID: 20812010, PMCID: PMC3018234. Martins MA, Wilson NA, Reed JS, Ahn CD, Klimentidis YC, Allison DB, Watkins DI. T-cell correlates of vaccine efficacy after a heterologous simian immunodeficiency virus challenge. J Virol. 2010 May; 84(9):4352-65. Epub 2010 Feb 17. PMID: 20164222, PMCID: PMC2863752.