Signals that establish and maintain HIV latency

建立和维持 HIV 潜伏期的信号

基本信息

批准号：
10394879
负责人：
Andrew J Henderson
金额：
$ 43.63万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-08 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394879
关键词：
AIDS/HIV problem Adaptor Signaling Protein Address Antigen Receptors Biochemical Process Biomedical Engineering CD28 gene Cell Cycle Progression Cell physiology Cells Chromatin Complex Cytoskeleton Data Dendritic Cells Engineering Event Genetic Transcription HIV HIV Infections HIV-1 Infection Interruption Lead Ligands Maps Mediating Molecular Mutation Pathway interactions Phosphoric Monoester Hydrolases Phosphotransferases Population Process Receptor Signaling Role Signal Transduction Structure T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Time Transcription Elongation Virus acute infection cellular targeting chimeric antigen receptor experimental study innovation insight interdisciplinary approach latent infection nanoparticle novel receptor recruit tool transcription factor transmission process virological synapse

项目摘要

PROJECT SUMMARY Long-lived latently infected cells present a major obstacle to curing HIV infection; however, the upstream biochemical processes and signal transduction events that favor active HIV replication versus latent infection are poorly understood. We hypothesize that quality of signals at the time of infection is critical for establishing HIV latency. To investigate how signals contribute to productive or latent HIV infection we will use chimeric antigen receptors to modulate signaling at the time of infection. In addition, we will explore the cross talk between T cell receptor signaling cascades and those delivered across the virological synapse during cell-cell transmission of HIV. We are proposing the following three specific aims: 1) how does differential signaling influence HIV-1 infection of T cells; 2) identifying signaling events that are required for HIV infection; and 3) determine whether antigen receptor signal strength at the virological synapse influences HIV infection. In addition to the hypothesis, innovative aspects of this proposal include the interdisciplinary approach, which uses cellular, molecular and bioengineering tools to identify key regulatory networks that influence HIV infection. These studies will provide new insights into key regulatory networks that govern the establishment of HIV infection and latency. Furthermore, understanding the minimal requirements for T cell signaling and HIV infection will potentially identify novel cellular targets which could be manipulated in an effort to alter the size of the latent reservoir and the course of HIV/AIDS progression.

项目摘要长寿的潜在感染细胞是治愈HIV感染的主要障碍。但是，上游有利于主动HIV复制与潜在感染的生化过程和信号转导事件是理解不佳。我们假设感染时信号的质量对于建立艾滋病毒至关重要潜伏期。为了调查信号如何促进生产性或潜在的HIV感染，我们将使用嵌合抗原受体在感染时调节信号传导。此外，我们将探索T细胞之间的串扰受体信号传导级联以及在细胞细胞传播过程中跨病毒式突触传递的级联艾滋病病毒。我们提出以下三个特定目标：1）差异信号如何影响HIV-1 T细胞的感染； 2）识别HIV感染所需的信号事件； 3）确定是否病毒学突触处的抗原受体信号强度会影响HIV感染。除了假设该提案的创新方面包括使用细胞，分子和分子的跨学科方法生物工程工具以识别影响艾滋病毒感染的关键监管网络。这些研究将提供对控制艾滋病毒感染和潜伏期的关键监管网络的新见解。此外，了解T细胞信号传导和HIV感染的最低要求可能会识别可以操纵的新型细胞靶标，以改变潜在储层的大小和艾滋病毒/艾滋病进展的过程。