Signals that establish and maintain HIV latency

项目摘要 长寿命的潜伏感染细胞是治愈HIV感染的主要障碍;然而， 与潜伏感染相比，有利于HIV活跃复制的生化过程和信号转导事件， 不太了解。我们假设感染时信号的质量对于建立HIV是至关重要的 延迟。为了研究信号如何促进生产性或潜伏性HIV感染，我们将使用嵌合抗原 受体来调节感染时的信号传导。此外，我们将探讨T细胞之间的串扰 受体信号级联和那些在细胞-细胞传递过程中通过病毒突触传递的信号级联， 艾滋病。我们提出了以下三个具体目标：1）差异信号如何影响HIV-1 感染T细胞; 2）鉴定HIV感染所需的信号传导事件;和3）确定是否 病毒突触上抗原受体信号强度影响HIV感染。除了假设之外， 这项建议的创新方面包括跨学科的方法，它使用细胞，分子和 生物工程工具，以确定影响艾滋病毒感染的关键调控网络。这些研究将提供 对控制HIV感染和潜伏期建立的关键调控网络的新见解。 此外，了解T细胞信号传导和HIV感染的最低要求将有可能确定 新的细胞目标，可以操纵，以改变大小的潜在水库和 艾滋病病毒/艾滋病的发展过程。

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.