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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：
10626867
负责人：
Mudit Tyagi
金额：
$ 23.4万
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/10626867
关键词：
Address Anti-HIV Therapy Area Autopsy Binding Binding Sites Biological Models Blood Vessels Brain CD4 Positive T Lymphocytes Cells Central Nervous System 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 Knowledge acquisition Long Terminal Repeats Lymphocyte Lymphoid Cell Macrophage Maintenance Mediating Microglia Modification Molecular Myelogenous Myeloid Cells Nuclear Paper Patients Phase Play Productivity Proviruses Public Health Publishing Research Rest Role Series Site Specimen Structure Targeted Research Testing Time Viral reservoir brain cell cell type chromatin modification design epigenetic silencing experimental study gene repression genetic corepressor histone modification inhibitor innovation knock-down latent HIV reservoir 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.

项目总结：虽然静息记忆CD4+ T细胞是公认的最长寿的