Discovery and Targeting of HIV-1 Associated Antigens

描述(由申请人提供)： 在寻找区别人类白细胞抗原I类感染细胞的HIV-1多肽时，我们发现许多宿主来源的多肽是HIV-1感染细胞所独有的。在目标1中，我们计划发现人类白细胞抗原I类提呈的宿主多肽可以区分HIV-1感染细胞。使用一种独特的免疫蛋白质组学方法，我们将对HIV-1不能抗原性变化的靶点进行分类。在发现了区分感染细胞的宿主多肽/人类白细胞抗原复合体后，我们接下来将继续研究这些复合体的免疫靶向。HIV-1感染细胞的人类白细胞抗原所呈现的靶向宿主多肽的一个令人担忧的问题是自身免疫；T细胞反应(包括记忆反应)可能靶向未感染细胞的宿主多肽。在目标2中，我们将获得模拟T细胞受体对多肽/人类白细胞抗原复合体(TCR模拟或TCRm抗体)的特异性的单抗。目标是被动地给予这些TCRm抗体，以靶向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。综上所述，我们将应用一种成熟的免疫蛋白质组学方法来识别未实现的人类白细胞抗原提呈的宿主多肽，以区分HIV-1感染细胞。此外，我们将用一种新的抗体TCRm靶向HIV-1特异性宿主多肽。这些新型抗体将在细胞系、原代人PBMC和针对原代HIV-1分离株的抗病毒效果方面进行系统测试。最终目标是测试被动注射TCRm抗体是否会影响HIV-1的复制，同时绕过靶向宿主表位的自身免疫后果。) 公共卫生声明：艾滋病毒已经能够躲避或击败直接针对病毒的免疫反应。我们假设，间接靶向HIV感染的细胞可以阻止病毒的传播。这项研究的目标是首先确定受感染细胞特有的变化，然后通过用一类新的抗体靶向受感染的细胞来间接攻击艾滋病毒。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.