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.

项目概要 艾滋病毒感染者 (PLWH) 可以通过抗逆转录病毒疗法 (ART) 得到有效治疗，但对于大多数人来说，尽快 当抗逆转录病毒治疗停止后，艾滋病毒会在几周内迅速反弹，但在极少数个体中，这称为治疗后。 控制者（PTC），艾滋病毒是由免疫介导的机制控制的，病毒反弹是如何被抑制的。 这种情况的发生目前仍知之甚少，PTC 中与病毒控制有关的一种免疫细胞。 在 ART 中断期间，自然杀伤 (NK) 细胞可以快速响应并杀死受感染的细胞。 经典先天免疫反应的一部分，但最近也被认为能够 拥有针对先前感染（包括艾滋病毒感染）的“记忆”。这种“记忆”被认为部分是介导的。 通过表观遗传机制了解 PTC 中 NK 细胞的类型和特征，以及它们是否与其他细胞不同。 更好地了解这些细胞是迈向非控制器（NC）的第一步。 了解如何控制艾滋病毒并利用它们进行治疗。 深入表征 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) 之前识别 NK 细胞上的生物标志物，预测 HIV 缓解。 其次，在 PTC 中去除 ART 后，NK 细胞（包括记忆 NK 细胞亚群）有助于控制 HIV。 我们将使用 CHAMP 研究中临床匹配的 PTC 和 NC 的纵向样本、ATI 样本、 在 ATI 后的早期（12 周内）和晚期（24 周后）时间点，我们将使用质谱流式细胞仪。 (CyTOF) 确定 PTC 和 NC 之前和之前的 NK 细胞亚群的表型和效应功能 在ATI之后，在目标2中，我们将使用多重单细胞RNAseq和单细胞ATACseq来鉴定转录。 以及治疗中断后来自 PTC 与 NC 的记忆和非记忆 NK 细胞的表观遗传特征。 了解能够介导 HIV 缓解的免疫反应为开发 治愈艾滋病毒的新疗法同样重要的是预测艾滋病毒缓解的非侵入性生物标志物。 更安全的治疗中断试验涉及这两个方面，特别关注 NK 细胞， 强大的免疫效应器，其介导艾滋病毒缓解的潜力尚未得到充分研究。