INVESTIGATION OF AUTOSTIMULATORY PATHWAYS REGULATING HIV

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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.