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.

抽象的单核细胞/巨噬细胞谱系细胞中的持续性HIV-1感染，例如大脑，肠道，淋巴样组织或脂肪组织形成不足的病毒储存库，可以防止根除HIV-1，甚至如果可以解决CD4+ T细胞中的储层。但是，除了潜在的HIV-1感染T细胞外，尚未详细介绍髓样细胞潜伏期潜伏期的生物分子控制。我们证明了艾滋病毒的潜在 1感染的单核细胞/巨噬细胞从正常的2N染色体转变为4N染色体状态。这与先前描述最活跃巨噬细胞的过渡的报告一致结核分枝杆菌感染到多倍体状态，表明4N转变是一种自然机制巨噬细胞在病原体反应中。多倍体不仅已知会增加对许多人的抵抗力挑战原本会导致细胞死亡，但也会触发非线性转录组效应，这破坏适当的细胞信号传导，我们建议是HIV-1无法建立主动感染的一部分。非- 在比较全基因组转录组特征（RNA- 不同的潜在HIV-1感染单核细胞克隆的Seq），这些克隆表现出广泛的连环异质性。然而，尽管具有广泛的转录组异质性，但潜在的HIV-1感染巨噬细胞共享一个小的在转录组（RNA-SEQ）和蛋白质组水平（Kinome Analysis）处的常见生物分子特征改变。我们将磷酸酶PPM1A确定为该潜伏控制签名的关键要素。 PPM1A的调制表达控制巨噬细胞中的活性HIV-1感染，调节了巨噬细胞对HIV的敏感性 1诱导细胞死亡，并改变了髓样细胞建立潜在感染的能力。因此针对ppm1a 有潜力提供新的治疗途径，以消除巨噬细胞中的HIV-1水库。这应用将有助于我们对髓样固有抗病毒反应的基本分子理解细胞受到控制，以及PPM1A活性的治疗调制如何有助于消除通常，髓样细胞中的持续性HIV-1储存剂，通常是脑居民小胶质细胞中的。