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

描述(申请人提供)：人类白细胞抗原B*5701与缓慢发展为艾滋病有关。虽然人类白细胞抗原B*5701限制了HIV-1编码表位对CD8+T细胞的呈递，但目前尚不清楚人类白细胞抗原B*5701是如何发挥其保护作用的。在这项提案中，我们将探索来自HIV-1感染细胞的自身表位的HLA-B*5701呈递在控制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HLAI类限制性自身表位的表面呈递。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改变。虽然这种现象已经有了很好的记录，但自我表位在HIV-1感染的整体免疫反应和对宿主的长期保护中所起的作用却完全未知。肿瘤特异性抗原的上调，如Mart 1，是一个已经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多肽冲击的自体树突状细胞在体内培养，然后在过继治疗策略中回输到患者体内，以增强正在进行的CTL反应。总之，这些数据表明，有必要进一步探索自身表位在确定艾滋病毒-1疾病进展速度方面的作用，并将其作为根除艾滋病毒-1感染细胞的治疗战略的潜在目标。这一方案中的实验将验证我们的假设，即对自身抗原的CTL反应通过增强现有的对病毒抗原的CTL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。为了验证这一假说，我们打算：1)鉴定HIV-1感染上调的人类白细胞抗原B*5701限制性自身表位，2)研究HIV-1感染激发的自身表位是否在体内产生人类白细胞抗原限制性CTL，目的3)评价体外启动的人类白细胞抗原A*0201和人类白细胞抗原B*5701限制性自身表位特异性CD8+T细胞的CTL功能。与公共卫生相关：这些实验可以为治疗策略的发展提供一个独特的途径，从而使艾滋病毒-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.