Generation of highly differentiated NK cells to act in synergy with broadly neutralizing antibodies to reduce the SIV reservoir and establish viral control in absence of ART

生成高度分化的 NK 细胞，与广泛中和抗体协同作用，减少 SIV 储存库，并在没有 ART 的情况下建立病毒控制

• 批准号: 10883005
• 负责人: Mirko Paiardini
• 金额: $ 81.28万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-22 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10883005
• 关键词: Abnormal Cell; African Green Monkey; Animals; Antibody Therapy; Antibody-Dependent Enhancement; Automobile Driving; B-Lymphocytes; Biological Assay; Blood; CD8B1 gene; Cells; Collaborations; Complex; Coupled; DNA; Data; Development; Disease remission; Drug or chemical Tissue Distribution; Education; Effector Cell; Environment; Exhibits; FCGR3B gene; Fc Receptor; Frequencies; Gastrointestinal tract structure; Generations; Goals; HIV; Immune; Immunotherapy; In Situ; Infection; Inflammation; Inflammatory; Intercept; Interruption; Intervention; Kinetics; Lymphoid; Lymphoid Tissue; Macaca mulatta; Maintenance; Measures; Mediating; Modeling; Natural Killer Cells; Oncology; Pathogenicity; Peptides; Persons; Phenotype; Positioning Attribute; Pre-Clinical Model; Production; Proliferating; Property; Recording of previous events; Reporting; Research Personnel; SIV; T-Lymphocyte; Testing; Time; Tissues; Viral; Viral Load result; Viral Physiology; Viral reservoir; Virus; Virus Diseases; Virus Replication; Withholding Treatment; Work; antibody-dependent cell cytotoxicity; antiretroviral therapy; cell killing; cohort; cytokine; cytotoxic; cytotoxicity; design; experience; genome-wide; in vivo; innovation; insight; interleukin-21; interleukin-21 receptor; lymph nodes; neutralizing antibody; neutralizing vaccine; neutrophil; preservation; prevent; receptor; response; synergism; transcriptome; transcriptome sequencing; vaccine efficacy; viral rebound; virus host interaction

PROJECT SUMMARY/ABSTRACT Lymph nodes and the gastrointestinal tract are major tissue viral reservoirs in people living with HIV and treated with antiretroviral treatment (ART). A distinguishing feature of SIV infection in African green monkeys (AGMs), a natural host species for SIV, is the absence of viral dissemination in the lymphoid B-cell follicle (BCF) and the presence of strong NKcell-mediated control of viral replication in the T-cell zone and BCF of secondary lymphoid tissues (SLT). In SIVagm-infected AGMs, we recently identified the expansion of NK cells with a terminally-differentiated phenotype expressing (i) high levels of CD16, an activating Fc receptor that mediates antibody-dependent cellular cytotoxicity (ADCC), and (ii) low levels of NKG2a, an inhibitory receptor, that modulates NK cell education via interactions with MHC-E. This terminally-differentiated NK cell (NKTD) subset (NKG2alowCD16+) exhibited adaptive-like properties and, due at least in part to reduced NKG2a expression, showed high cytolytic activity against target cells presenting SIV-Env peptides in the context of MHC-E. The formation of adaptive NKTD cells was blocked in SIVmac-infected rhesus macaques (RMs) in favor of a subset (NKG2ahiCD16+) with pro-inflammatory function, such as production of IFN, a cytokine also known for its capacity to increase MHC-E expression on target cells. Remarkably, in a separate cohort of SIVmac-infected, ART-treated RMs, we demonstrated that AGM-like profiles of adaptive NKTD cells are rescued via treatment with interleukin-21 (IL-21). In IL-21 treated RMs, the frequency and responsiveness of the adaptive NKTD cells to target cells presenting SIV peptides in the context of MHC-E strongly correlated with a reduction of SIV DNA in the gut, lower levels of replication competent virus in SLT, and a delay in viral rebound following ART interruption. In Aim 1 of this proposal we will define (I) the mechanisms driving the formation and activity of adaptive NKTD cells, such as cytokine environment and lymphoid inflammation; (II) their tissue distribution; and (III) ADCC capacity. In addition to NK cells, the impact of IL-21 will be investigated in T-cells and other immune cells that can respond to IL-21. In Aim 2, we will assess whether and to what extent the combination of IL-21-induced NKTD cells and a cocktail of anti-SIV broadly neutralizing antibodies (bNAbs) facilitates, through ADCC-mediated clearance of infected cells, a reduction of viral burden and control of viral rebound following ART interruption. Specifically, in SIVmac-infected, ART-treated RMs, the “differentiate, target, and kill” approach will allow differentiation of the NKTD cells with IL-21 followed by targeting of cells harboring reactivated virus with bNAbs. Using a model reproducing the complex virus-host interactions occurring in people living with HIV, we expect that the rescue of NK cell terminal differentiation will promote robust ADCC activity, which will synergize with the selective targeting of viral reservoirs that reactivate following ATI, thus leading to prolonged ART-free remission.

项目摘要/摘要 淋巴和胃肠道是艾滋病毒携带者和 接受抗逆转录病毒治疗(ART)。非洲绿猴SIV感染的一个显著特征 SIV的自然宿主物种(AGMS)是指淋巴B细胞滤泡中没有病毒传播 (Bcf)和存在强大的NK细胞介导的病毒复制控制在T细胞区和bcf。 次级淋巴组织(SLT)。在SIVagm感染的AGM中，我们最近发现了NK细胞的扩张 具有终末分化的表型表达(I)高水平的CD16，激活的Fc受体 介导抗体依赖的细胞细胞毒性(ADCC)，以及(Ii)低水平的NKG2A，一种抑制性受体， 通过与MHC-E的相互作用来调节NK细胞的教育。这种终末分化的NK细胞(NKTD) 子集(NKG2alowCD16+)表现出类似自适应的特性，并且至少部分由于NKG2a的减少 表达的SIV-Env多肽对呈递SIV-Env多肽的靶细胞显示出高的细胞杀伤活性 MHC-ESIVmac感染恒河猴(RMS)中适应性NKTD细胞的形成被阻断 倾向于具有促炎功能的亚群(NKG2ahiCD16+)，例如产生干扰素，一种细胞因子 众所周知，它有能力增加靶细胞上MHC-E的表达。值得注意的是，在另一组 SIVmac感染，ART治疗的RMS，我们证明了适应性NKTD细胞的AgM样轮廓被挽救 经白介素21(IL-21)治疗。在IL-21处理的RMS中， NKTD细胞对呈递SIV多肽的靶细胞的适应性与MHC-E密切相关 肠道中SIV DNA减少，SLT中具有复制能力的病毒水平较低，以及病毒反弹延迟 在艺术中断之后。在本提案的目标1中，我们将定义(I)驱动形成的机制 和适应性NKTD细胞的活性，如细胞因子环境和淋巴炎症；(Ii)其组织 分配；以及(Iii)ADCC能力。除了NK细胞外，还将研究IL-21对T细胞的影响 以及其他可以对IL-21做出反应的免疫细胞。在目标2中，我们将评估是否以及在多大程度上 IL-21诱导NKTD细胞与抗SIV广谱中和抗体(BNAbs)的结合 通过ADCC介导的受感染细胞清除，有助于减少病毒负担和控制病毒 艺术中断后的反弹。具体地说，在感染SIVmac、接受ART治疗的RMS中，“分化， 靶向和杀伤“的方法将允许NKTD细胞用IL-21分化，然后靶向细胞 携带带有bNAbs的重新激活的病毒。使用一个模型再现复杂的病毒与宿主的相互作用 发生在HIV携带者身上，我们预计挽救NK细胞的终末分化将促进 强大的ADCC活性，这将与选择性靶向重新激活的病毒库协同作用 在ATI之后，从而导致长期的无ART缓解。