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Control of latent/persistent HIV-1 infection in macrophages/microglia: A key role for the phosphatase PPM1A

控制巨噬细胞/小胶质细胞中潜伏/持续的 HIV-1 感染：磷酸酶 PPM1A 的关键作用

基本信息

批准号：
10447757
负责人：
OLAF KUTSCH
金额：
$ 18.56万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447757
关键词：
Acute Address Adipose tissue Antiviral Response Brain Bypass CD4 Positive T Lymphocytes Cell Cycle Cell Death Cell Line Cell physiology Cells Chromosomes Chronic Clone Cells DNA DNA Damage Data Devices Drug Combinations Elements Event Exposure to Failure Gatekeeping Gene Silencing Genetic Transcription Genome Granuloma HIV HIV-1 Half-Life Heterogeneity Infection Inflammatory Intervention Karyotype determination procedure Lymphoid Tissue Macaca Microglia Modeling Molecular Myelogenous Myeloid Cells Natural Immunity Pathogenesis Pathway Analysis Patients Pharmacology Phosphoric Monoester Hydrolases Phosphorylation Polyploidy Predisposition Primary Infection Proliferating Protein Dephosphorylation Proteins Proteome Publications RNA Reporter Reporting Resistance Role SIV Signal Pathway Signal Transduction Stains Stimulus System T-Lymphocyte TBK1 gene TLR2 gene TP53 gene Therapeutic Tissues Tuberculosis Up-Regulation Viral reservoir Virus Diseases Virus Latency active control antiretroviral therapy arm cellular targeting clinically relevant design experimental study follow-up genetic manipulation genome-wide improved interest knock-down latent infection macrophage monocyte novel therapeutics overexpression pathogen phosphoproteomics prevent programs response success transcriptome transcriptome sequencing transcriptomics

项目摘要

ABSTRACT Persistent HIV-1 infection in cells of the monocyte/macrophage lineage in tissues such as the brain, gut, lymphoid tissues, or adipose tissue forms an under-investigated viral reservoirs that will prevent eradication of HIV-1, even if the reservoir in CD4+ T cells could be addressed. However, other than for latently HIV-1 infected T cells, so far the biomolecular control of latency in myeloid cells has not been detailed. We demonstrate that latently HIV- 1 infected monocyte/macrophages transition from a normal 2n chromosome set to a 4n chromosome state. This is consistent with a previous report that describes the transition of the most active macrophages combating Mycobacterium tuberculosis infection to a polyploid state, indicating that 4n transition is a natural mechanism of macrophages during their pathogen response. Polyploidy is not only known to increase resistance to many challenges that would otherwise result in cell death, but also triggers non-linear transcriptomic effects, which disrupt proper cell signaling and we propose are part of the inability of HIV-1 to establish active infection. Non- linear transcriptomic effects become obvious in the comparison of genome-wide transcriptomic signatures (RNA- seq) of different latently HIV- 1 infected monocyte clones, which show extensive inter-clonal heterogeneity. However, despite this extensive transcriptomic heterogeneity, latently HIV-1 infected macrophages share a small common altered biomolecular signature at the transcriptome (RNA-seq) and proteome level (kinome analysis). We identified the phosphatase PPM1A as a key element of this latency control signature. Modulation of PPM1A expression controlled active HIV-1 infection in macrophages, regulated the susceptibility of macrophages to HIV- 1 induced cell death, and altered the capacity of myeloid cells to establish latent infection. Thus targeting PPM1A has the potential to provide a new therapeutic avenue to eradicate HIV-1 reservoirs in macrophages. This application will contribute to our basic molecular understanding of how the intrinsic antiviral response of myeloid cells is controlled and how therapeutic modulation of PPM1A activity could contribute to the elimination of persistent HIV-1 reservoirs in myeloid cells in general and specifically in brain-resident microglia.

抽象的大脑、肠道、淋巴等组织中的单核细胞/巨噬细胞系细胞持续感染 HIV-1 组织或脂肪组织形成了一个未经充分研究的病毒库，它将阻止 HIV-1 的根除，甚至如果可以解决 CD4+ T 细胞中的储存库问题。然而，除了潜伏 HIV-1 感染的 T 细胞之外，迄今为止，骨髓细胞潜伏期的生物分子控制尚未详细说明。我们证明，潜在的 HIV- 1 个受感染的单核细胞/巨噬细胞从正常的 2n 染色体组转变为 4n 染色体状态。这与之前的一份报告一致，该报告描述了最活跃的巨噬细胞的转变结核分枝杆菌感染至多倍体状态，表明 4n 转变是结核分枝杆菌感染的自然机制巨噬细胞在病原体反应期间。众所周知，多倍体不仅可以增加对许多疾病的抵抗力否则会导致细胞死亡的挑战，但也会引发非线性转录组效应，这破坏正常的细胞信号传导，我们认为这是 HIV-1 无法建立主动感染的部分原因。非- 线性转录组效应在全基因组转录组特征（RNA- seq）的不同潜伏HIV-1感染的单核细胞克隆，显示出广泛的克隆间异质性。然而，尽管存在这种广泛的转录组异质性，潜伏 HIV-1 感染的巨噬细胞共享一个小的转录组异质性。转录组（RNA-seq）和蛋白质组水平（激酶组分析）的常见生物分子特征改变。我们确定磷酸酶 PPM1A 是这种延迟控制特征的关键元素。 PPM1A 的调制表达控制巨噬细胞中的主动HIV-1感染，调节巨噬细胞对HIV-1的易感性 1 诱导细胞死亡，并改变骨髓细胞建立潜伏感染的能力。因此针对 PPM1A 有潜力提供一种新的治疗途径来根除巨噬细胞中的 HIV-1 病毒库。这应用将有助于我们对骨髓的内在抗病毒反应如何进行基本的分子理解细胞受到控制以及 PPM1A 活性的治疗调节如何有助于消除 HIV-1 持续存在于骨髓细胞中，特别是大脑中的小胶质细胞中。