Protective roles of CTL responses to HIV-1 associated self epitope

描述（由申请人提供）：HLA-B*5701与艾滋病进展缓慢有关。虽然很多人都关注HLA- B*5701限制HIV-1编码表位向CD8+ t细胞的呈递，但HLA- B*5701如何发挥其保护作用尚不清楚。在本研究中，我们将探讨来自HIV-1感染细胞的HLA-B*5701自身表位在控制HIV-1感染中的潜在作用。像其他病毒一样，HIV-1感染细胞可以增加hla - I类限制性自身表位的表面呈现。作为对应激的生理反应的一部分，蛋白质迅速上调和降解，导致受感染细胞的自我表位呈递库发生改变。虽然这一现象有充分的文献记载，但自我表位的呈现在HIV-1感染的整体免疫反应和宿主的长期保护中所起的作用是完全未知的。肿瘤特异性抗原（如mat1）的上调是一个已被用于设计治疗策略的过程。来自癌症患者的CD8+ t细胞与代表肿瘤特异性表位的肽脉冲的自体树突状细胞一起在体内培养，然后以过继治疗策略注入患者体内，以增强正在进行的CTL反应。这些数据表明，需要进一步探索自身表位在决定HIV-1疾病进展速度中的作用，以及作为根除HIV-1感染细胞的治疗策略的潜在靶点。本提案中的实验将验证我们的假设，即CTL对自身抗原的反应通过增强现有的CTL对病毒抗原的反应，在HIV-1病毒血症的整体长期免疫控制中发挥重要作用。为了验证这一假设，我们计划：目的1)表征HIV-1感染上调的HLA-B*5701限制性自身表位；目的2)研究HIV-1感染诱导的自身表位是否在体内产生hla限制性CTL；目的3)通过肽脉冲单核细胞衍生的树突状细胞评估体外引物HLA-A*0201和HLA-B*5701限制性自身表位特异性CD8+ t细胞的CTL功能。公共卫生相关性：通过为开发治疗策略提供独特的途径，这些实验可以使HIV-1感染者受益。

DESCRIPTION (provided by applicant): HLA-B*5701 is associated with slow progression to AIDS. While much attention has focused on the HLA- B*5701 restricted presentation of HIV-1 encoded epitopes to CD8+ T-cells, it remains unclear how HLA- B*5701 exerts it protective influence. In this proposal, we will explore the potential role of HLA-B*5701 presentation of self-epitopes derived from HIV-1 infected cells in controlling HIV-1 infection. Like other viruses, HIV-1 infection of a cell can increase the surface presentation of HLA-class I restricted self-epitopes. As part of the physiological response to stress, proteins become quickly up-regulated and degraded resulting in an altered repertoire of self-epitope presentation by the infected cell. While this phenomenon is well documented, the role played by presentation of self-epitopes in the overall immune response to HIV-1 infection and long-term protection of the host are completely unknown. The up-regulation of tumor-specific antigens, such as MART 1, is a process that has been capitalized upon for the design of therapeutic strategies. CD8+ T-cells from the cancer patient are cultured in vivo with autologous dendritic cells pulsed with peptides representing the tumor-specific epitope then infused back into the patient in an adoptive therapy strategy to augment ongoing CTL responses. Together these data indicate that further exploration is warranted into the role of self- epitopes in determining the rate of HIV-1 disease progression and as a potential target for therapeutic strategies to eradicate HIV-1 infected cells. Experiments within this proposal will test our hypothesis that CTL responses to self-antigens play a significant role in the overall long-term immunologic control of HIV-1 viremia by augmenting existing CTL responses to viral antigens. To test this hypothesis, we intend to: Aim 1) Characterize HLA-B*5701 restricted self-epitopes up-regulated by HIV-1 infection, Aim2) Investigate whether self epitopes, elicited by HIV-1 infection, generate HLA-restricted CTL in vivo, and Aim 3) Evaluate CTL functions of in vitro primed HLA-A*0201, and HLA-B*5701 restricted self-epitope-specific CD8+ T-cells by peptide pulsed monocyte derived dendritic cells. PUBLIC HEALTH RELEVANCE: The experiments could benefit HIV-1 infected individuals by providing a unique avenue for the development of therapeutic strategies.