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; 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.

项目摘要 患有艾滋病毒（PLWH）的人可以通过抗逆转录病毒疗法（ART）有效治疗，但对于大多数人来说 随着艺术的停止，艾滋病毒在几周内迅速弹起。但是，在罕见的人中，称为后处理 控制器（PTC），HIV受免疫介导的机制控制，病毒反弹被抑制。如何 这种情况仍然很糟糕。 PTC中一种隐含在病毒控制中的一种免疫电池 在艺术中​​断期间，自然杀手（NK）细胞。这些细胞可以迅速响应并杀死感染细胞，因为 经典先天免疫反应的一部分，但最近也有人建议能够 携带“记忆”，以抵抗先前感染，包括艾滋病毒。这种“记忆”被认为部分是介导的 通过表观遗传机制。 NK细胞在PTC中的类型和特征，以及它们是否与这些区别不同 在非控制器（NCS）中，尚不清楚。更好地理解这些细胞是迈向的第一步 了解他们如何控制艾滋病毒并利用治疗。该提议的目的是 深层表征PTC和非控制器（NCS）中NK细胞的功能和效应子功能，并 在预测HIV缓解的分析治疗中断（ATI）之前，鉴定NK细胞上的生物标志物。我们 假设NK细胞（包括内存NK细胞子集）有助于控制ART在PTC中去除ART后控制HIV。 我们将使用来自临床匹配的PTC和NC的纵向样品，来自Champ研究，采样ATI， 在ATI之后的时间点（24周后）和晚期（在24周之后）的早期（在12周内）。在AIM 1中，我们将使用质量细胞术 （cytof）确定来自PTC和NCS的NK细胞子集的表型和效应子功能 ati之后。在AIM 2中，我们将使用多路复用的单细胞RNASEQ和单细胞Atacseq识别转录 在治疗中断后，来自PTCS与NCS的记忆和非内存NK细胞的表观遗传特征。 了解能够介导HIV缓解的免疫调查会为开发的途径 治愈艾滋病毒的新型疗法。同样必不可少的是非侵入性生物标志物，可预测HIV的缓解 安全治疗中断试验。该建议涉及这两个方面，专门针对NK细胞， 强大的免疫生效者对介导HIV缓解的潜力得到了众所周知。