Characterizing the virologic and immunologic signatures of HIV exceptional control

项目总结/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， 个体“异常控制”是一种相关但独特的自然艾滋病毒控制表型， 关注艾滋病治疗社区。本提案的总体目标是确定和描述 个人表现出特殊的控制血液和组织，并启动研究，寻求了解 实现这一点的机制。我们有几个相互关联的假设：（1）例外控制器 在淋巴组织中对HIV复制的控制比典型的精英控制者更强， 外周血中的控制水平，（2）特殊的控制者将比典型的控制者具有更少的全身炎症 精英控制者和ART治疗个体，这些水平将与未感染个体相似，（3） 与典型的精英控制者相比，已经启动ART然后中断治疗的特殊控制者 在高度监测的情况下，残留病毒血症、炎症或免疫标志物不会发生变化， activation.为了调查这些假设，我们将开始确定自然艾滋病毒控制者在加州大学旧金山分校 SCOPE队列在没有ART的情况下，在大量患者中具有非常低水平的完整前病毒HIV DNA， 外周血CD 4 + T细胞;这些将是假定的特殊控制者。那些拥有更高 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，我们将执行一个横截面 一项使用肠道活检和淋巴结组织抽吸物测量HIV储存库大小和分布的研究 在稳态，比较特殊的控制器与典型的精英控制器。在目标2中，我们将执行交叉- 通过测量免疫激活的异常控制的免疫学后果的截面研究 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志物。我们 将比较特殊的控制器在稳态与典型的精英控制器，非控制器的艺术， 未受感染的人。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， 发生在宿主首次遇到反弹病毒的最早时间点（“拦截”）。我们预计 中断治疗的特殊控制者将证明这些标志物在 与其他群体形成对比。如果我们的假设是正确的，我们预计，特殊的控制器将 与典型的精英控制者和非控制者相比， 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疗法中获益。如果是这种情况， 将导致进一步的机制研究，以了解这一控制水平的实现过程， 可能会为进一步的工作提供信息，以开发艾滋病毒“缓解”模型。

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.”