Activation-induced Non-responsiveness causes HIV Prog.

描述（由申请方提供）：HIV-1保护的免疫相关性未知，使得有效、预防性和治疗性疫苗的基本原理设计变得困难。该提案将研究HIV特异性CD 8 +T细胞中激活诱导的无反应性（AINR）的诱导是否会导致HIV-1慢性感染者的疾病进展。我们的初步数据显示，HIV-1慢性感染导致HIV特异性T细胞中AINR的诱导。此外，控制慢性HIV-1感染的个体（长期非进展者，LTNP）拥有对AINR具有抗性的HIV特异性T细胞。因此，HIV特异性CD 8 + T细胞中AINR的诱导可能是病毒控制丧失和进展为AIDS的原因。在目的1中，我们将使用IFN-γ ELISpot、多色（11色）流式细胞术和蛋白质组学技术表征AINR CD 8 + HIV特异性T细胞的功能表型，以确定AINR状态下哪些效应子功能（除增殖能力外）受到损害。此外，在整个感染过程中对这些T细胞应答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 CD 8 + T细胞的出现是否与疾病进展相关。在目标2中，我们将使用体外感染性测定来确定HIV特异性AINR CD 8 + T细胞是否在其防止病毒复制的能力方面受到损害。我们将确定是否存在AINR HIV特异性T细胞在体内影响病毒的进化，通过测序区域的自体病毒，对应于抗原决定簇识别的AINR CD 8 + T细胞。此外，我们将尝试逆转AINR状态，并确定这是否会增强对病毒感染的控制。在目标3中，我们将确定有助于诱导AINR的因素。由于拟议的研究将潜在地表征保护免受HIV-1疾病进展的免疫相关性，因此它们将对慢性感染个体的治疗干预和HIV疫苗的合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.