Activation-induced Non-responsiveness causes HIV Prog.

描述(由申请人提供)：针对HIV-1的免疫保护相关尚不清楚，这使得有效的、预防的和治疗性的疫苗的理论设计变得困难。这项建议将调查在HIV-1慢性感染者中，诱导HIV特异性CD8+T细胞的激活诱导无反应性(AINR)是否导致疾病进展。我们的初步数据显示，慢性感染HIV-1会导致HIV特异性T细胞中AINR的诱导。此外，控制慢性HIV-1感染的个人(长期非进展者，LTNP)拥有对AINR具有抵抗力的HIV特异性T细胞。因此，在HIV特异性CD8+T细胞中诱导AINR可能是病毒失去控制和发展为艾滋病的原因。在目标1中，我们将利用干扰素-γ-ELISpot、多色(11色)流式细胞术和蛋白质组学技术来表征AINR CD8+HIV特异性T细胞的功能表型，以确定在AINR状态下哪些效应功能(除了增殖能力)受到损害。此外，对感染过程中这些T细胞反应的纵向分析将使我们能够确定AINR何时出现在自然感染的背景下，以及AINR CD8+T细胞的出现是否与疾病进展相关。在目标2中，我们将使用体外传染性分析来确定HIV特异性AINR CD8+T细胞在阻止病毒复制方面是否受到损害。我们将通过对AINR CD8+T细胞识别的表位对应的自体病毒区域的测序来确定体内AINR HIV特异性T细胞的存在是否影响病毒的进化。此外，我们将尝试逆转AINR状态，并确定这是否会加强对病毒感染的控制。在目标3中，我们将确定导致AINR的因素。由于拟议的研究将潜在地表征防止艾滋病毒-1疾病进展的免疫相关性，它们将对慢性感染者的治疗干预和艾滋病毒疫苗的基本原理设计产生深远的影响。

DESCRIPTION (provided by applicant): The immune correlates of protection against HIV-1 are unknown making rationale design of efficacious, prophylactic and therapeutic vaccines difficult. This proposal will investigate whether induction of Activation- Induced Non-Responsiveness (AINR) in HIV-specific CD8+T cells leads to disease progression in persons chronically infected with HIV-1. Our preliminary data show that chronic infection with HIV-1 leads to the induction of AINR in HIV-specific T cells. Furthermore, individuals who are controlling chronic HIV-1 infection (long term non-progressors, LTNP) possess HIV-specific T cells that are resistant to AINR. Thus, induction of AINR in HIV-specific CD8+ T cells may be the cause of loss of viral control and progression to AIDS. In Aim 1 we will characterize the functional phenotype of AINR CD8+ HIV-specific T cells to determine which effector functions (apart from proliferative ability) are compromised in the AINR sate using IFN-gamma ELISpot, polychromatic (11 color) flow cytometry and proteomics technologies. Furthermore, longitudinal analysis of these T cell responses throughout the course of infection will allow us to determine when AINR appears in the context of natural infection and whether appearance of AINR CD8+ T cells correlates with disease progression. In Aim 2, we will determine whether HIV-specific AINR CD8+ T cells are compromised in their ability to prevent viral replication using in vitro infectivity assays. We will ascertain whether the presence of AINR HIV-specific T cells in vivo influences viral evolution by sequencing regions of the autologous virus that correspond to epitopes recognized by AINR CD8+ T cells. In addition, we will attempt to reverse the AINR state and determine if this leads to enhanced control of viral infection. In Aim 3, we will identify factors that contribute to induction of AINR. Since the proposed studies will potentially characterize an immune correlate of protection from HIV-1 disease progression they will have far reaching implications on therapeutic intervention in chronically-infected individuals and rationale design of HIV vaccines.