Characterizing ART-free NK cell-mediated control of HIV infection in people living with HIV

描述 HIV 感染者中无 ART 的 NK 细胞介导的 HIV 感染控制

• 批准号: 10535192
• 负责人: Nadia R Roan
• 金额: $ 28.35万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10535192
• 关键词: ATAC-seq; Address; Aftercare; Alleles; Biological Markers; Blood; Cells; Chromatin; Clinical; Cytolysis; Cytomegalovirus; Cytometry; Data; Development; Differentiation Antigens; Disease remission; Epigenetic Process; Exhibits; FCGR3B gene; Flow Cytometry; Frequencies; Genes; Genetic Transcription; HIV; HIV Antibodies; HIV Infections; Helper-Inducer T-Lymphocyte; Immune; Immune response; Immune system; Individual; Infection; Inflammatory; Innate Immune Response; Innate Immune System; Interferons; Interleukin-15; Interruption; KLRD1 gene; Lead; Mediating; Memory; Methods; NCAM1 gene; Natural Killer Cells; Outcome; Patients; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Receptor Cell; Research Design; Role; Sampling; Specimen; Time; Viral; Viremia; Virus; Virus Replication; Withdrawal; antiretroviral therapy; clinical biomarkers; co-infection; cytokine; cytotoxic CD8 T cells; demographics; humanized mouse; insight; lymph nodes; memory recall; novel; novel therapeutics; predictive marker; receptor; response; single-cell RNA sequencing; transcriptome; transcriptomics; viral rebound

PROJECT SUMMARY People living with HIV (PLWH) can be treated effectively with antiretroviral therapy (ART) but for most, as soon as ART is stopped, HIV quickly rebounds within weeks. However, in rare individuals, called post-treatment controllers (PTCs), HIV is controlled by immune-mediated mechanisms and viral rebound is suppressed. How this occurs remains poorly understood. One type of immune cell in PTCs that has been implicated in viral control during ART interruption is Natural Killer (NK) cells. These cells can rapidly respond to and kill infected cells as part of a classical innate immune response, but more recently has also been suggested to be capable of harboring “memory” against prior infection including that by HIV. This “memory” is thought to be in part mediated through epigenetic mechanisms. The types and features of NK cells in PTCs, and whether they differ from those in non-controllers (NCs), is not known. A better understanding of these cells is the first step towards understanding how they can control HIV and be harnessed for therapy. The objective of this proposal is to deeply characterize the features and effector functions of NK cells in PTCs and non-controllers (NCs), and to identify biomarkers on NK cells prior to analytical treatment interruption (ATI) that predict HIV remission. We hypothesize that NK cells, including memory NK cell subsets, help to control HIV after ART is removed in PTCs. We will use longitudinal samples from clinically-matched PTCs and NCs from the CHAMP study, sampled ATI, and at early (within 12 weeks) and late (after 24 weeks) timepoints after ATI. In Aim 1, we will use mass cytometry (CyTOF) to determine the phenotypes and effector functions of NK cell subsets from PTCs and NCs before and after ATI. In Aim 2, we will use multiplexed single-cell RNAseq and single-cell ATACseq to identify transcriptional and epigenetic signatures of memory and non-memory NK cells from PTCs vs. NCs after treatment interruption. Understanding immune responses capable of mediating HIV remission provides an avenue for development of novel therapeutics to cure HIV. Equally essential are non-invasive biomarker(s) that predict HIV remission for safer treatment interruption trials. This proposal addresses both these aspects focusing specifically on NK cells, powerful immune effectors that are much understudied with regards to their potential to mediate HIV remission.

项目总结 艾滋病毒携带者(PLWH)可以用抗逆转录病毒疗法(ART)有效地治疗，但对大多数人来说，尽快 随着抗逆转录病毒疗法的停止，艾滋病毒在几周内迅速反弹。然而，在罕见的个体中，称为治疗后 控制者(PTCs)，HIV由免疫调节机制控制，病毒反弹被抑制。多么 这种情况的发生仍然知之甚少。PTCS中与病毒控制有关的一种免疫细胞 在ART中断期间，是自然杀伤(NK)细胞。这些细胞可以迅速对感染的细胞做出反应并杀死它们 是典型的先天免疫反应的一部分，但最近也被认为能够 对先前的感染，包括艾滋病毒感染，怀有“记忆”。这种“记忆”被认为在一定程度上是 通过表观遗传机制。PTC中NK细胞的类型和特点，以及它们是否与 在非控制器(NCS)中，是未知的。更好地了解这些细胞是迈向 了解他们如何控制艾滋病毒并被利用进行治疗。这项建议的目的是 深入研究PTC和非控制者(NC)中NK细胞的特征和效应功能，并 在分析治疗中断(ATI)前确定预测HIV缓解的NK细胞上的生物标志物。我们 假设在PTCs中去除ART后，NK细胞，包括记忆性NK细胞亚群，有助于控制HIV。 我们将使用来自CHAMP研究的临床匹配的PTC和NCS的纵向样本，样本ATI， 在ATI后早期(12周内)和晚期(24周后)时间点。在目标1中，我们将使用质量细胞术 (CyTOF)检测PTCs和NCS中NK细胞亚群的表型和效应功能 在ATI之后。在目标2中，我们将使用多路复用的单细胞RNAseq和单细胞ATACseq来鉴定转录 治疗中断后PTCS与NCS的记忆性和非记忆性NK细胞的表观遗传学特征。 了解能够介导HIV缓解的免疫反应为发展HIV提供了一条途径 治愈艾滋病毒的新疗法。同样重要的是非侵入性生物标志物(S)，它可以预测艾滋病病毒的缓解 更安全的治疗中断试验。这项提案涉及这两个方面，特别是NK细胞， 强大的免疫效应器，就其调节艾滋病毒缓解的潜力而言，研究得很少。