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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：为了开发艾滋病毒疫苗，我们将确定细胞毒性和辅助性T细胞的其他表位，并利用这些信息开发用于以下免疫反应的独特试剂。 HLA-B27-和-B57-阳性HIV感染的人长期以来与HIV复制的控制相关，这意味着CD 8 + T细胞应答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SIVmac 239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。 因此，它是持续感兴趣的映射表位成功的疫苗，以及呈现它们的等位基因，作为一种手段，以更充分地了解对SIV的免疫反应，并给SIV研究人员更多的工具和疫苗开发的目标。 在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。 已经开发了一种算法来整合这种新的结合位点，预测的肽已经被定义和排序，并且结合研究正在进行中，以确定以最高亲和力结合的肽。 在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。 这些研究所需的所有细胞系现在都已经到位，并且已经开发了具有这种基因型的感染动物的列表。 我们还定义了Mamu-B *48（频率10%）、Mamu-B *52（频率7%）和B*29的基序。 我们已经为Mamu-A*07定义了表位，并且已经发表了一项针对该等位基因的研究。 在2010年，我们将定义Mamu的基序-B *12、-B*30、-B*47、-B*64和 A*06。 在2009年和2010年，我们已经开始映射表位和等位基因存在于成功的疫苗从我们的研究发表在2009年6月。 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。 最后，我们现在开始对MHC II类等位基因进行基序测定。 我们通过观察精英控制者和成功接种者的CD 4 + T细胞反应，确定了30多个SIV定义的MHC II类等位基因和肽对。 这项研究还使用了来自MHC分型设施和免疫学和病毒学服务单位，Elispot和流式细胞仪的资源。 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，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.疫苗诱导的细胞反应控制异源攻击后猴免疫缺陷病毒的复制。J Virol。2009年7月;83（13）：6508-21. Epub 2009年4月29日。 PMID：19403685 Loffredo JT，Sidney J，Bean AT，比尔DR，Bardet W，Wahl A，Hawkins OE，Piaskowski S，Wilson NA，Hildebrand WH，Watkins DI，Sette A.与免疫缺陷病毒复制的精英控制相关的两种MHC I类分子Mamu-B*08和HLA-B*2705结合具有序列相似性的肽。 免疫学杂志2009年6月15日;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和Nef特异性CD 4 + T细胞在感染后早期识别并抑制感染巨噬细胞中的SIV复制。 美国国家科学院2009年6月16日;106（24）：9791-6。Epub 2009年5月28日。 PMID：19478057

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