Discovery and Targeting of HIV-1 Associated Antigens

描述（由申请人提供）： 在寻找区分感染细胞的HLA I类的HIV-1肽时，我们发现许多宿主衍生的肽对HIV-1感染细胞是独特的。在目标1中，我们提出发现区分HIV-1感染细胞的HLA I类呈递宿主肽。使用一种独特的免疫蛋白质组学方法，我们将目录HIV-1不能抗原性变化的目标。在发现了区分感染细胞的宿主肽/HLA复合物之后，我们接下来将追求这些复合物的免疫靶向。靶向由HIV-1感染细胞的HLA呈递的宿主肽的关注点是自身免疫; T细胞应答（包括记忆应答）可能靶向未感染细胞上的宿主肽。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）。目标是被动施用这些TCRm抗体以靶向HIV-1感染的细胞。在目的3中，将测试这些TCRm抗体的抗病毒活性。总之，我们将应用一种成熟的免疫蛋白质组学方法来鉴定未实现的HLA呈递宿主肽，以区分HIV-1感染的细胞。此外，我们将用一类新的抗体靶向HIV-1特异性宿主肽：TCRm。这些新型抗体将在细胞系、原代人PBMC和原代HIV-1分离株中进行系统性抗病毒作用试验。最终目标是测试TCRm抗体的被动施用是否会影响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感染细胞可以阻断病毒的传播。这项研究的目的是首先确定受感染细胞的独特变化，然后通过用一类新的抗体靶向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.