Characterizing the virologic and immunologic signatures of HIV exceptional control

描述 HIV 异常控制的病毒学和免疫学特征

• 批准号: 10461189
• 负责人: Michael Joseph Peluso
• 金额: $ 20.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-03 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461189
• 关键词: Address; Aspirate substance; Biometry; Biopsy; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Characteristics; Chronic; Clinic; Clinical; Communities; Cross-Sectional Studies; DNA; Development; Disease Progression; Disease remission; Exhibits; Fibrosis; Foundations; Frequencies; Funding; Future; Genetic Transcription; Genome; Goals; HIV; HIV Infections; Image; Immune System Diseases; Immune system; Immunologics; Individual; Inflammation; Inflammatory; Intercept; Interruption; Laboratories; Lymph Node Tissue; Lymphoid; Lymphoid Tissue; Magnetic Resonance Imaging; Measurable; Measures; Methods; Modeling; Monitor; Morbidity - disease rate; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Positron-Emission Tomography; Prevalence; Process; Prospective Studies; Protocols documentation; RNA; Residual state; Risk; Sampling; Scientist; Standardization; T-Cell Activation; Tissues; Training; Viral reservoir; Viremia; Virus; Virus Replication; Work; adaptive immune response; antiretroviral therapy; base; circulating biomarkers; cohort; experimental study; imaging approach; immune activation; inflammatory marker; interest; microbial; mortality; novel; peripheral blood; programs; prospective; radiotracer; systemic inflammatory response; translational physician; translational scientist; viral rebound

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.”

项目概要/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得到自由缓解 个人。 “异常控制”是自然艾滋病毒控制的一种相关但独特的表型，目前具有很大的作用 艾滋病毒治疗界的兴趣。该提案的总体目标是确定并描述 个人对血液和组织表现出特殊的控制能力，并启动研究来了解 实现这一目标的机制。我们有几个相互关联的假设：（1）特殊控制者 尽管与典型的精英控制者相比，他们对淋巴组织中的 HIV 复制表现出更强的控制力 外周血的控制水平，（2）特殊的控制者比典型的控制者有更少的全身炎症 精英控制者和接受 ART 治疗的个体，这些水平将与未感染个体的水平相似，(3) 与典型的精英控制者不同，杰出的控制者启动了 ART 然后中断治疗 在高度监控的环境中，残留病毒血症、炎症或免疫标志物不会出现任何变化 激活。为了研究这些假设，我们将首先确定 UCSF 中的自然 HIV 控制者 SCOPE 队列中，在没有接受 ART 治疗的情况下，大量的完整 HIV 病毒前病毒 DNA 水平非常低 外周血CD4+T细胞；这些将是假定的特殊控制者。具有较高水平的个人 完整原病毒 DNA 水平将被视为典型的精英控制者。在目标 1 中，我们将进行横截面分析 研究利用肠道活检和淋巴结组织抽吸来测量艾滋病毒储存库的大小和分布 在稳态下，将特殊控制器与典型的精英控制器进行比较。在目标 2 中，我们将执行一个交叉 通过测量免疫激活来研究异常控制的免疫学后果 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 将在稳态下将特殊控制器与典型的精英控制器、ART 上的非控制器进行比较，以及 未感染的个体。在目标 3 中，我们将分析在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”）。我们预计 中断治疗的特殊控制者将证明这些标记物在 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者将 与典型的精英控制者和非控制者相比表现出显着差异，将 与未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受益。如果是这样的话，那么 将导致进一步的机制研究，以了解实现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信息。