Characterizing the virologic and immunologic signatures of HIV exceptional control

项目摘要/摘要 典型的精英控制艾滋病毒感染不再被认为是抗逆转录病毒治疗(ART)的最佳模式- 由于转录活性增加、慢性炎症和免疫功能障碍而导致的自由缓解 个人。“特殊控制”是艾滋病毒自然控制的一种相关但不同的表型，现在非常重要。 引起艾滋病治疗社区的兴趣。这项提案的首要目标是确定和描述 在血液和组织中表现出特殊控制的个体，并开始研究试图了解 实现这一目标的机制。我们有几个相互关联的假设：(1)特殊控制器 与典型的精英控制器相比，显示出对淋巴组织中艾滋病毒复制的更好控制，尽管具有可比性 外周血液的控制水平，(2)特殊的控制员的全身炎症将比典型的更少 精英控制者和接受抗逆转录病毒治疗的人，这些水平将与未感染的人相似，(3) 与典型的精英控制器形成对比的是，特殊控制器启动了ART，然后中断治疗 在高度监测的环境中，残留病毒血症、炎症或免疫的标志物不会发生变化 激活。为了研究这些假说，我们将首先从加州大学旧金山分校的天然HIV控制者开始 范围队列在缺乏抗逆转录病毒治疗的情况下，在大量 外周血中的CD4+T细胞；这些将是假定的特殊控制者。拥有更高收入的个人 完整的前病毒DNA水平将被认为是典型的精英控制者。在目标1中，我们将执行横截面 用肠道活检和淋巴组织抽吸物测量HIV储存库的大小和分布的研究 在稳态时，将优秀控制器与典型精英控制器进行比较。在目标2中，我们将执行一个交叉- 通过测量免疫活性来研究特殊控制的免疫学后果 PET-MR成像以及炎症和免疫系统激活的可溶性和细胞相关标记物。我们 将稳定状态下的特殊控制器与典型的精英控制器、ART上的非控制器以及 未受感染的个体。在目标3中，我们将分析在一项外部资助的前瞻性研究中收集的样本。 HIV控制者和非控制者中断ART以确定病毒学和免疫学变化 发生在宿主第一次遇到反弹病毒的最早时间点(“拦截”)。我们期待着 中断治疗的特殊控制者将不会显示这些标志物在 与其他组形成对比。如果我们的假设是正确的，我们预计特殊的控制器将 展示出与典型精英控制器和非控制器相比的显著差异，将 与没有感染艾滋病毒的人没有区别，也不会从抗逆转录病毒治疗中受益。如果是这样的话，它 将导致进一步的机械研究，以了解达到这种控制水平的过程，以及 可能会为开发艾滋病毒“缓解”模型的进一步工作提供参考。

PROJECT SUMMARY/ABSTRACT Typical elite control of HIV infection is no longer considered an optimal model for antiretroviral therapy (ART)- free remission due to increased transcriptional activity, chronic inflammation, and immune dysfunction in these individuals. “Exceptional control” is a related but distinct phenotype of natural HIV control that is now of great interest to the HIV cure community. The overarching objective of this proposal is to identify and characterize individuals exhibiting exceptional control in blood and tissues, and to initiate studies that seek to understand the mechanism by which this is achieved. We have several inter-related hypotheses: (1) exceptional controllers exhibit greater control over HIV replication in lymphoid tissues than typical elite controllers, despite comparable levels of control in peripheral blood, (2) exceptional controllers will have less systemic inflammation than typical elite controllers and ART-treated individuals and these levels will be similar to those in uninfected individuals, (3) in contrast to typical elite controllers, exceptional controllers who have initiated ART and then interrupt therapy in a highly monitored setting will exhibit no change in markers of residual viremia, inflammation, or immune activation. To investigate these hypotheses, we will begin by identifying natural HIV controllers in the UCSF SCOPE cohort who in the absence of ART have very low levels of intact proviral HIV DNA in a large number of peripheral blood CD4+ T cells; these will be the putative exceptional controllers. Individuals who have higher levels of intact proviral DNA will be considered typical elite controllers. In Aim 1, we will perform a cross-sectional study using gut biopsies and lymph node tissue aspirates to measure the size and distribution of the HIV reservoir at steady-state, comparing exceptional controllers with typical elite controllers. In Aim 2, we will perform a cross- sectional study of the immunologic consequences of exceptional control by measuring immune activation with PET-MR imaging and soluble and cell-associated markers of inflammation and immune system activation. We will compare exceptional controllers at steady-state with typical elite controllers, non-controllers on ART, and uninfected individuals. In Aim 3, we will analyze samples collected in an externally funded prospective study of HIV controllers and non-controllers interrupting ART to determine the virologic and immunologic changes that occur at the earliest timepoints when the host first encounters rebounding virus (the “intercept”). We anticipate that exceptional controllers interrupting therapy will demonstrate no substantial increase in these markers in contrast with the other groups. If our hypotheses are correct, we expect that exceptional controllers will demonstrate significant differences compared with typical elite controllers and non-controllers, will be indistinguishable from people without HIV infection, and will not have benefitted from ART. If this is the case, it will lead to further mechanistic studies to understand the process by which this level of control is achieved and might inform further work to develop a model for HIV “remission.”