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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：为了开发HIV疫苗，我们将确定更多的细胞毒性和辅助T细胞表位，并利用这些信息开发用于后续免疫反应的独特试剂。 长期以来，人类白细胞抗原B27和B57阳性的HIV感染者一直与控制HIV复制有关，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阳性的印度恒河猴控制着SIVmac239的复制，成为慢性期病毒血症低于1000vRNA拷贝/毫升的精英控制者。因此，绘制成功疫苗接种者呈现的表位以及呈现这些表位的等位基因图是持续感兴趣的，作为一种手段，更全面地了解SIV的免疫应答，并为SIV研究人员提供更多的工具和疫苗开发的目标。 在2008-2009年间，我们为Mamu-B*22定义了一个基序，其频率为29%，这是一个相当高频率的等位基因。已经开发了一种算法来结合这个新的结合位点，预测的多肽已经被定义和排序，结合研究正在进行中，以确定与最高亲和力结合的多肽。2010年初，我们将在感染SIV的动物身上测试这些多肽，以确定哪些多肽实际呈现给T细胞。这些研究所需的所有细胞系现在都已就位，并已开发出具有该基因型别的感染动物名单。 我们还定义了MAMU-B*48(频率10%)、MAMU-B*52(频率7%)和B*29的基序。我们已经为Mamu-A*07定义了表位，并已经发表了一项以该等位基因为特征的研究。2010年，我们将定义玛木-B*12、-B*30、-B*47、-B*和A*06的图案。 在2009年和2010年，我们已经开始绘制我们在2009年6月发表的研究中成功接种疫苗的人的表位和等位基因。在这项研究中，8名疫苗接种者中有6人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。我们通过观察精英控制员和成功接种者中存在的CD4+T细胞反应，定义了30多个SIV定义的MHC II类等位基因和多肽对。 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： 威尔逊·纳、Keele BF、Reed JS、Piaskowski SM、MacNair CE、Bett AJ、梁X、Wang F、Thoryk E、Heidecker GJ、Citron MP、黄L、林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、颤栗JW、Casimiro Dr、Shaw GM、Hahn BH、Watkins DI。疫苗诱导的细胞反应控制异种攻击后猴免疫缺陷病毒的复制。J·维罗尔。2009年7月；83(13)：6508-21。EPub 2009年4月29日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两个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HLAB*2705，结合具有序列相似性的多肽。j免疫。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，Leén EJ，Friedrich TC，Wilson NA，Hiraoka A，Watkins DI。GAG和Nef特异性的CD4+T细胞在感染后早期识别和抑制感染巨噬细胞中的SIV复制。S学报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