Susceptibility of antigen-specific CD4 T cells to HIV: implications for HIV vacci

描述：为了更好地了解HIV感染的发病机制，一个中心问题是记忆CD4T细胞是如何被HIV感染并逐渐耗尽的。目前对HIV感染对不同病原体或抗原特异性的CD4T细胞的影响知之甚少。探索这一领域对于更好地理解不同的 艾滋病患者的机会性感染。此外，确定对HIV具有“抵抗力”的疫苗特异性CD4T细胞的功能群体对HIV疫苗设计至关重要。 我们建立了一种新的系统来研究抗原特异性的CD4T细胞对HIV的易感性，并发现不同的抗原特异性的CD4T细胞对HIV感染的敏感性有明显的差异。我们的初步数据显示，与破伤风类毒素(TT)和白色念珠菌(Candida)特异性的CD4T细胞相比，巨细胞病毒(CMV)特异性的CD4T细胞对进入后HIV限制的R5和X4HIV都具有高度的抵抗力。我们的微阵列分析发现了一种新的病毒RNA传感器IFIT1，它在CMV特异性的CD4T细胞中高度上调。重要的是，在我们正在进行的实验中，我们表明Ifit1的过表达显著抑制了A3R5 CD4T细胞系中的HIV感染。基于已经产生的数据，我们假设IFIT 1可以抑制人类原代CD4T细胞中的HIV感染，并且IFIT 1的差异表达调节抗原特异性CD4T细胞对HIV的许可。 我们进一步建议将新的系统和观察扩展到临床艾滋病毒疫苗研究。HIV优先感染疫苗产生的CD4T细胞会降低疫苗诱导免疫的效率。我们的假设是，保护性HIV疫苗将诱导一种疫苗特异性的CD4T细胞，这些细胞对HIV不容易敏感，而不同的候选HIV疫苗(例如，不同的载体)会诱导不同的疫苗特异性CD4T细胞的表型，这可能会显著影响它们对HIV的敏感性。我们会检测外周血 来自三个已完成的艾滋病毒疫苗试验的单个核细胞样本：RV144(ALVAC)、RV158(MVA)和IPVC001(AD26)。我们的假设将针对两个特定目标：1)确定IFIT 1在调节人类抗原特异性CD4T细胞对HIV的敏感性中的作用，并进一步探索IFIT 1抑制HIV的机制；2)研究不同HIV疫苗诱导的抗原特异性CD4T细胞对HIV感染的敏感性及其在HIV疫苗试验中的相关表型。 拟议中的研究是探索性的，但预计将为以下方面提供新的见解：1)了解艾滋病患者CMV特异性T细胞免疫持续的机制；2)确定一种新的抗HIV分子，其抑制机制/途径以前未知，可能导致新的HIV疗法的开发；3)更好地了解疫苗产生的CD4T细胞免疫的质量，并提供关于是否以及如何通过HIV疫苗诱导功能性的、“抗HIV的”CD4T细胞的概念证明知识。

DESCRIPTION: A central question to better understanding the pathogenesis of HIV infection is how memory CD4 T cells are infected and progressively depleted by HIV. Little is currently known about the impact of HIV infection on CD4 T cells of different pathogen or antigen specificities. Exploring this area is important for better understanding of the timing of different opportunistic infections in AIDS patients. In addition, identification of a functional population o vaccine-specific CD4 T cells that is "resistant" to HIV is critical for HIV vaccine design. We have established a novel system for studying the susceptibility of antigen-specific CD4 T cells to HIV, and have found that different antigen-specific CD4 T cells manifest marked differences in susceptibility to HIV infection. Our preliminary data show that compared to CD4 T cells specific to tetanus toxoid (TT) and Candida albicans (Candida), which are permissive to HIV, cytomegalovirus (CMV)-specific CD4 T cells are highly resistant to both R5 and X4 HIV with post-entry HIV restriction. Our microarray analysis identified a novel viral RNA sensor, IFIT1 that is highly upregulated in CMV-specific CD4 T cells. Of importance, in our ongoing experiments, we show that over-expression of IFIT1 significantly inhibits HIV infection in A3R5 CD4 T cell line. Based on data already generated, we hypothesize that IFIT1 can inhibit HIV infection in human primary CD4 T cells and differential expression of IFIT1 regulates the permissiveness of antigen-specific CD4 T cells to HIV. We further propose to extend the novel system and observations to clinical HIV vaccine studies. Preferential infection of vaccine-generated CD4 T cells by HIV reduces the efficiency of vaccine-induced immunity. Our hypothesis is that a protective HIV vaccine would induce a type of vaccine-specific CD4 T cells that are "not readily susceptible" to HIV, and that different candidate HIV vaccines (e.g. different vectors) induce distinct phenotypes of vaccine-specific CD4 T cells that may significantly impact their sensitivities to HIV. We will test peripheral blood mononuclear cell samples from three completed HIV vaccine trials: RV144 (ALVAC), RV158 (MVA) and IPVC001 (Ad26). Our hypotheses will be addressed in 2 Specific Aims: 1) To determine the role of IFIT1 in regulating the susceptibility of human antigen-specific CD4 T cells to HIV and to further explore the mechanisms for inhibition of HIV by IFIT1; 2) To investigate the susceptibilities of different HIV vaccine-induced, antigen-specific CD4 T cells to HIV infection and the associated phenotypes in HIV vaccine trials. The proposed studies are exploratory, but expected to provide new insights to: 1) understand the mechanisms for the persistence of CMV-specific T cell immunity in AIDS patients; 2) identify a novel anti-HIV molecule with previously unidentified inhibitory mechanisms/pathways that could lead to the development of novel HIV therapies; 3) better understand the quality of vaccine-generated CD4 T cell immunity and to provide proof of concept knowledge on whether and how to induce functional, "HIV-resistant" CD4 T cells by an HIV vaccine.