INVESTIGATION OF AUTOSTIMULATORY PATHWAYS REGULATING HIV

描述：巨噬细胞在HIV-1的建立中起关键作用 感染和发展为艾滋病。受感染的巨噬细胞作为长寿的 许多组织中的病毒储存库。此外，这些细胞产生 炎症和细胞毒性因子，可能会影响的功能， 邻近的细胞和组织。本提案的总体目标是 研究导致细胞破坏的细胞和分子事件， 内皮细胞和巨噬细胞在这一过程中的作用。研究者 提出转录激活因子C/EBP β参与了 HIV-1感染时巨噬细胞基因表达失调， 巨噬细胞-内皮细胞相互作用，并有助于微 环境有利于HIV-1的复制。研究者使用 与人脐静脉内皮细胞共培养的原代巨噬细胞 （HUVEC）以更好地了解这些相互作用如何影响 HIV-1复制，以及识别可溶性因子和细胞表面 介导这些反应的分子。调查人员还将确定 巨噬细胞是否能诱导内皮细胞凋亡及 磷脂酰丝氨酸（PS）的内皮细胞表面。实验将 进行，以确定是否PS有助于招募感染 巨噬细胞的内皮细胞和永久的内皮细胞破坏。 最后，C/EBPbeta的重要性将通过表征 潜伏感染和未感染的单核细胞系的能力， 过表达C/EBP β或显性负性LIP，以与 内皮细胞

DESCRIPTION: Macrophages play a critical role in the establishment of HIV-1 infection and progression to AIDS. Infected macrophages serve as long-lived reservoirs for virus in many tissues. Furthermore, these cells produce inflammatory and cytotoxic factors that may influence the function of neighboring cells and tissues. The overall goal of this proposal is to investigate the cellular and molecular events that lead to breaching of the endothelilium and the role of macrophages in this process. The investigator proposes that the transcriptional activator C/EBPbeta is involved in disregulated macrophage gene expression during HIV-1 infection, altering macrophage-endothelial cell interactions, and contributing to a micro environment that is favorable for HIV-1 replication. The investigator uses primary macrophages co-cultured with human umbilical vein endothelial cells (HUVEC) to gain a better understanding of how these interactions influence HIV-1 replication, as well as to identify soluble factors and cell surface molecules that mediate these responses. The investigator will also determine whether macrophages can induce endothelial cell apoptosis and expression of phosphatidylserine (PS) on the endothelial cell surface. Experiments will be conducted to determine whether PS contributes to the recruitment of infected macrophages to the endothelium and perpetuates endothelial cell destruction. Finally, the importance of C/EBPbeta will be directly tested by characterizing the ability of latently infected and uninfected monocytic lines that overexpress C/EBPbeta or a dominant negative LIP to functionally interact with endothelial cells.