CBF-1 role in regulating HIV reservoir in microglial cells

CBF-1在调节小胶质细胞中HIV储存库中的作用

基本信息

批准号：
10403065
负责人：
Mudit Tyagi
金额：
$ 19.5万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10403065
关键词：
Address Anti-HIV Therapy Area Autopsy Binding Binding Sites Biological Models Brain CD4 Positive T Lymphocytes Cells Chromatin Structure Complex Drops Economic Burden Enzymes Epigenetic Process Exploratory/Developmental Grant Failure Functional disorder Gene Expression Generations Genetic Transcription Goals Grant HIV HIV Long Terminal Repeat HIV-1 HIV-associated neurocognitive disorder Heterochromatin Highly Active Antiretroviral Therapy Human Individual Inflammation Investigation Knowledge Long Terminal Repeats Lymphocyte Lymphoid Cell Maintenance Mediating Microglia Modification Molecular Myelogenous Myeloid Cells Neuraxis Nuclear Paper Patients Phase Play Proviruses Public Health Publishing Research Rest Role Series Site Specimen Structure Targeted Research Testing Time Viral reservoir base brain cell cell type chromatin modification design epigenetic silencing experimental study gene repression genetic corepressor histone modification inhibitor innovation knock-down latent HIV reservoir macrophage memory CD4 T lymphocyte novel novel therapeutics promoter reactivation from latency recruit targeted treatment therapeutic target transcription factor treatment optimization

项目摘要

Project Summary: Although the resting memory CD4+ T cells are the best-recognized long-lived reservoirs of latent HIV provirus, it is now well accepted that the myeloid cells, especially of the central nervous system (CNS)- -including perivascular macrophages and microglial cells--can also contribute to viral reservoirs. The molecular mechanisms relevant to HIV latency are primarily defined by analyzing HIV latency in latently infected CD4+ lymphoid cells. However, very little is known about HIV latency/persistence in myeloid cells. Notably, the presence of HIV-harboring myeloid cells in the CNS are documented to be the key factor contributing to CNS inflammation and promoting HIV-associated neurocognitive disorder (HAND) in HIV patients. Microglial cells are the main HIV reservoir in the CNS, yet a gap in the knowledge regarding our understanding of the molecular mechanisms that maintains HIV reservoirs in those cells. Our long term goal is identifying and characterizing the underlying molecular mechanisms that regulate HIV latency in microglial cells. The important role of CBF-1-mediated transcriptional inhibition during HIV latency is well established in lymphoid cells. The objective of this grant is to characterize the role of CBF-1 during HIV latency in microglial cells. Based on our published and preliminary findings, we have hypothesized that, similar to lymphocytes, in microglial cells CBF- 1 promotes HIV latency/slowdown by inducing the generation of transcriptionally-repressive heterochromatin structures at HIV LTR. Our rationale is that since HIV latency is primarily regulated at the transcriptional level, defining the precise mechanism(s) that regulate HIV transcription in microglial cells will offer new therapeutic opportunities to target HIV reservoirs in the CNS. In Aim 1, we will examine the role of CBF-1-induced epigenetic changes in restricting HIV transcription and their eventual impact on the establishment and the maintenance phases of HIV latency. In Aim 2, we will characterize the corepressor complexes that CBF-1 recruits at HIV LTR and their functional significance in promoting HIV reservoir in microglial cells. Upon conclusion, we will be able to define the CBF-1-mediated mechanisms that facilitate the establishment and maintenance of HIV latency in microglial cells. These studies will also provide a well-defined therapeutic target in the form of CBF-1 and its corepressor complexes in order to relieve multiple repressive epigenetic modifications simultaneously. Proposed research is innovative because it uses human primary microglial cells, and a novel ex vivo model system for HIV latency in microglial cells that, for the first time, allows the studies of the molecular correlates for HIV entry and exit into latency in microglial cells, which is otherwise an impossible task due to insufficient availability of brain autopsy specimens. This contribution is significant since the identified mechanisms, which regulate HIV transcription and latency in microglial cells, will facilitate the designing of optimized therapies targeting CNS reservoirs of HIV, contributing to cure approaches.

项目摘要：尽管静息内存CD4+ T细胞是最公认的长寿命库潜在的HIV病毒，现在已被公认为髓样细胞，尤其是中枢神经系统（CNS） - - 包括血管周围巨噬细胞和小胶质细胞 - can也有助于病毒储存。与HIV潜伏期相关的分子机制主要通过分析潜在的HIV潜伏期来定义感染的CD4+淋巴样细胞。但是，关于髓样细胞中的HIV潜伏期/持续性知之甚少。值得注意的是，中枢神经系统中的HIV-HARBORING髓样细胞的存在被记录为促成的关键因素艾滋病毒患者中CNS炎症并促进与HIV相关的神经认知障碍（手）。小胶质细胞细胞是中枢神经系统中的主要艾滋病毒水库在这些细胞中维持艾滋病毒储量的分子机制。我们的长期目标是确定和表征调节小胶质细胞中HIV潜伏期的基本分子机制。重要在淋巴样细胞中，CBF-1介导的在HIV潜伏期期间的转录抑制作用已很好地确定。这该赠款的目的是表征CBF-1在小胶质细胞中HIV潜伏期中的作用。基于我们发表和初步发现，我们假设在小胶质细胞CBF-中类似于淋巴细胞 1通过诱导转录抑制异染色质的产生来促进艾滋病毒潜伏/放缓 HIV LTR的结构。我们的理由是，由于HIV潜伏期主要在转录级别进行调节，所以定义调节小胶质细胞中HIV转录的精确机制将提供新的治疗有机会针对中枢神经系统中的艾滋病毒储量。在AIM 1中，我们将检查CBF-1诱导的表观遗传学的作用限制艾滋病毒转录及其最终对机构和维护的影响的变化艾滋病毒潜伏期的阶段。在AIM 2中，我们将表征HIV LTR的CBF-1招募的COREPRESSPRESSOR络合物以及它们在促进小胶质细胞中促进HIV储库中的功能意义。结论，我们将能够定义CBF-1介导的机制，以促进艾滋病毒潜伏期的建立和维持小胶质细胞。这些研究还将以CBF-1及其形式提供明确定义的治疗靶点 CorePressor复合物可以同时缓解多种抑制性表观遗传修饰。拟议的研究具有创新性，因为它使用了人类的原代小胶质细胞和一种新型的离体模型小胶质细胞中HIV潜伏期的系统，这是第一次允许研究分子相关的研究艾滋病毒进入并退出小胶质细胞的潜伏期，否则，由于不足，这是不可能的任务脑尸检标本的可用性。这种贡献很重要，因为已确定的机制调节小胶质细胞中的HIV转录和潜伏期，将有助于设计优化的疗法针对艾滋病毒的中枢神经系统储藏，有助于治愈方法。