Discovery and Targeting of HIV-1 Associated Antigens

描述（由申请人提供）： 在寻找区分受感染细胞的 HLA I 类的 HIV-1 肽时，我们发现许多宿主衍生的肽是 HIV-1 感染细胞所独有的。在目标 1 中，我们建议发现能够区分 HIV-1 感染细胞的 HLA I 类呈递宿主肽。使用独特的免疫蛋白质组学方法，我们将对 HIV-1 不能发生抗原变异的靶标进行分类。在发现了区分感染细胞的宿主肽/HLA 复合物后，我们接下来将研究这些复合物的免疫靶向。针对 HIV-1 感染细胞的 HLA 呈递的宿主肽的一个关注点是自身免疫； T 细胞反应（包括记忆反应）可能以未感染细胞上的宿主肽为目标。在目标 2 中，我们将获得模拟 T 细胞受体对肽/HLA 复合物的特异性的单克隆抗体（TCR 模拟物或 TCRm 抗体）。目标是被动地施用这些 TCRm 抗体来靶向 HIV-1 感染细胞。在目标 3 中，将测试这些 TCRm 抗体的抗病毒活性。总之，我们将应用经过验证的免疫蛋白质组学方法来识别未实现的 HLA 呈递的宿主肽，以区分 HIV-1 感染的细胞。此外，我们将用一类新的抗体来靶向 HIV-1 特异性宿主肽：TCRm。这些新型抗体将系统地测试细胞系、原代人类 PBMC 和原代 HIV-1 分离株的抗病毒作用。最终目标是测试 TCRm 抗体的被动给药是否会影响 HIV-1 复制，同时绕过靶向宿主表位的自身免疫后果。） 公共卫生声明：艾滋病毒能够逃避或击败直接针对该病毒的免疫反应。我们假设间接靶向 HIV 感染细胞可以阻止病毒传播。这项研究的目标是首先识别受感染细胞特有的变化，然后通过用一类新型抗体针对受感染细胞来间接攻击 HIV。我们打算针对病毒所需的因素，而不是病毒本身。

DESCRIPTION (provided by applicant): While searching for HIV-1 peptides that distinguish the HLA class I of infected cells, we found that a number of host-derived peptides are unique to HIV-1 infected cells. In aim 1 we propose to discover HLA class I presented host peptides that distinguish HIV-1 infected cells. Using a unique immunoproteomics approach we will catalog targets that HIV-1 cannot antigenically vary. Having discovered host peptide/HLA complexes that distinguish infected cells, we will next pursue the immune targeting of these complexes. A concern in targeting host peptides presented by the HLA of HIV-1 infected cells is autoimmunity; T cell responses (including memory responses) might target host peptides on uninfected cells. In aim 2 we will derive monoclonal antibodies that mimic the T cell receptor's specificity for peptide/HLA complexes (TCR mimics or TCRm antibodies). The goal is to passively administer these TCRm antibodies for the targeting of HIV-1 infected cells. In aim 3 the anti-viral activity of these TCRm antibodies will be tested. In summary, we will apply a proven immunoproteomics approach to identify unrealized HLA presented host peptides that distinguish HIV-1 infected cells. Furthermore, we will target HIV-1 specific host peptides with a new class of antibodies: TCRm. These novel antibodies will be systematically tested for antiviral effects in cell lines, primary human PBMC and against primary HIV-1 isolates. The ultimate goal is to test whether passive administration of TCRm antibodies will impact HIV-1 replication while bypassing the autoimmune consequences of targeting host epitopes.) Public Health Statement: HIV has been able to elude or defeat immune responses that directly target the virus. We hypothesize that the indirect targeting of HIV infected cells can block transmission of the virus. The goal of this study is to first identify changes unique to the infected cell and to then indirectly attack HIV by targeting infected cells with a new class of antibodies. We intend to target factors that the virus requires rather than the virus itself.