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

描述：更好地了解 HIV 感染发病机制的一个核心问题是记忆 CD4 T 细胞如何被 HIV 感染并逐渐耗尽。目前对于 HIV 感染对不同病原体或抗原特异性的 CD4 T 细胞的影响知之甚少。探索这个领域对于更好地理解不同的时间安排非常重要 艾滋病患者的机会性感染。此外，鉴定对 HIV“具有抵抗力”的疫苗特异性 CD4 T 细胞功能群对于 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CD4 T细胞对HIV的易感性，并发现不同的抗原特异性CD4 T细胞对HIV感染的易感性存在显着差异。我们的初步数据表明，与破伤风类毒素（TT）和白色念珠菌（Candida）特异性的CD4 T细胞（允许HIV感染）相比，巨细胞病毒（CMV）特异性CD4 T细胞对R5和X4 HIV具有高度抵抗力，并且在HIV进入后受到限制。我们的微阵列分析发现了一种新型病毒 RNA 传感器 IFIT1，它在 CMV 特异性 CD4 T 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 的过度表达可显着抑制 A3R5 CD4 T 细胞系中的 HIV 感染。根据已经生成的数据，我们假设 IFIT1 可以抑制人类原代 CD4 T 细胞中的 HIV 感染，并且 IFIT1 的差异表达调节抗原特异性 CD4 T 细胞对 HIV 的许可程度。 我们进一步建议将新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CD4 T细胞会降低疫苗诱导免疫的效率。我们的假设是，保护性 HIV 疫苗会诱导一种对 HIV“不易敏感”的疫苗特异性 CD4 T 细胞，并且不同的候选 HIV 疫苗（例如不同的载体）会诱导疫苗特异性 CD4 T 细胞的不同表型，这可能会显着影响其对 HIV 的敏感性。我们将检测外周血 来自三个已完成的 HIV 疫苗试验的单核细胞样本：RV144 (ALVAC)、RV158 (MVA) 和 IPVC001 (Ad26)。我们的假设将在2个具体目标中得到解决：1）确定IFIT1在调节人类抗原特异性CD4 T细胞对HIV敏感性中的作用，并进一步探讨IFIT1抑制HIV的机制； 2) 研究不同HIV疫苗诱导的抗原特异性CD4 T细胞对HIV感染的敏感性以及HIV疫苗试验中的相关表型。 拟议的研究是探索性的，但预计将提供新的见解：1）了解艾滋病患者体内 CMV 特异性 T 细胞免疫持续存在的机制； 2) 鉴定出一种新型抗艾滋病毒分子，其具有先前未发现的抑制机制/途径，可能导致新型艾滋病毒疗法的开发； 3) 更好地了解疫苗产生的 CD4 T 细胞免疫的质量，并提供有关 HIV 疫苗是否以及如何诱导功能性“抗 HIV”CD4 T 细胞的概念验证知识。

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.