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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI046261-01A1
Application #
6147601
Study Section
Special Emphasis Panel (ZRG1-AARR-2 (01))
Program Officer
Plaeger, Susan F
Project Start
2000-06-01
Project End
2004-04-30
Budget Start
2000-06-01
Budget End
2001-04-30
Support Year
1
Fiscal Year
2000
Total Cost
$242,704
Indirect Cost
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
City
University Park
State
PA
Country
United States
Zip Code
16802
Kalantari, Parisa; Harandi, Omid F; Hankey, Pamela A et al. (2008) HIV-1 Tat mediates degradation of RON receptor tyrosine kinase, a regulator of inflammation. J Immunol 181:1548-55
Strasner, Amy B; Natarajan, Malini; Doman, Tom et al. (2008) The Src kinase Lck facilitates assembly of HIV-1 at the plasma membrane. J Immunol 181:3706-13
Gekonge, Bethsebah N; Schiralli, Gillian; Schlegel, Robert A et al. (2006) Signal transduction induced by apoptotic cells inhibits HIV transcription in monocytes/macrophages. J Leukoc Biol 80:953-60
Ragin, Melanie J; Hu, Jianfang; Henderson, Andrew J et al. (2005) A role for the Tec family kinase ITK in regulating SEB-induced interleukin-2 production in vivo via c-jun phosphorylation. BMC Immunol 6:19
Yang, Polung; Henderson, Andrew J (2005) Nef enhances c-Cbl phosphorylation in HIV-infected CD4+ T lymphocytes. Virology 336:219-28
Fan, Xiaoxuan; Krahling, Stephen; Smith, Douglas et al. (2004) Macrophage surface expression of annexins I and II in the phagocytosis of apoptotic lymphocytes. Mol Biol Cell 15:2863-72
Lee, Eileen S; Kalantari, Parisa; Tsutsui Section, Shigeki et al. (2004) RON receptor tyrosine kinase, a negative regulator of inflammation, inhibits HIV-1 transcription in monocytes/macrophages and is decreased in brain tissue from patients with AIDS. J Immunol 173:6864-72
Hogan, Tricia H; Nonnemacher, Michael R; Krebs, Fred C et al. (2003) HIV-1 Vpr binding to HIV-1 LTR C/EBP cis-acting elements and adjacent regions is sequence-specific. Biomed Pharmacother 57:41-8
Callahan, Melissa K; Halleck, Margaret S; Krahling, Stephen et al. (2003) Phosphatidylserine expression and phagocytosis of apoptotic thymocytes during differentiation of monocytic cells. J Leukoc Biol 74:846-56
Nonnemacher, Michael R; Hogan, Tricia H; Quiterio, Shane et al. (2003) Identification of binding sites for members of the CCAAT/enhancer binding protein transcription factor family in the simian immunodeficiency virus long terminal repeat. Biomed Pharmacother 57:34-40

Showing the most recent 10 out of 15 publications