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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 AIDS¹

Eileen S. Lee^2,3,*,, Parisa Kalantari^2,,, Shigeki Tsutsui, Alicia Klatt^,, Janet Holden, Pamela H. Correll^*,,, Christopher Power and Andrew J. Henderson^4,*,,

Graduate Programs in ^* Biochemistry, Microbiology and Molecular Biology, and Pathobiology, and Department of Veterinary Science, Pennsylvania State University, University Park, PA 16802; Departments of Clinical Neuroscience, Microbiology, and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada; and Department of Pathology, St. Paul’s Hospital, Vancouver, British Columbia, Canada

Activation of macrophages and microglia cells after HIV-1 infection and their production of inflammatory mediators contribute to HIV-associated CNS diseases. The mechanisms that initiate and maintain inflammation after HIV-1 infection in the brain have not been well studied. Furthermore, it is not understood why in HIV-associated CNS disease, macrophages and microglia are biased toward inflammation rather than production of mediators that control inflammation. We have focused on the receptor tyrosine kinase RON, a critical negative regulator of macrophage function and inflammation, to determine whether this receptor regulates HIV-1 expression. Overexpressing RON in monocytes/macrophages demonstrates that RON inhibits HIV-1 proviral transcription in part by decreasing the binding activity of NF-B to the HIV-1 long terminal repeat. Because macrophages and microglia cells are a critical reservoir for HIV-1 in the CNS, we examined brain tissues for RON expression and detected RON in astrocytes, cortical neurons, and monocytoid cells. RON was detected in all control patients who were HIV seronegative (n = 7), whereas six of nine brain samples obtained from AIDS patients exhibited reduced RON protein. These data suggest that RON initiates signaling pathways that negatively regulate HIV-1 transcription in monocytes/macrophages and that HIV-1 suppresses RON function by decreasing protein levels in the brain to assure efficient replication. Furthermore, HIV-1 infection would compromise the ability of RON to protect against inflammation and consequent CNS damage.

This article has been cited by other articles:

				P. Kalantari, O. F. Harandi, P. A. Hankey, and A. J. Henderson HIV-1 Tat Mediates Degradation of RON Receptor Tyrosine Kinase, a Regulator of Inflammation J. Immunol., July 15, 2008; 181(2): 1548 - 1555. [Abstract] [Full Text] [PDF]

				A. Klatt, Z. Zhang, P. Kalantari, P. A. Hankey, D. S. Gilmour, and A. J. Henderson The Receptor Tyrosine Kinase RON Represses HIV-1 Transcription by Targeting RNA Polymerase II Processivity J. Immunol., February 1, 2008; 180(3): 1670 - 1677. [Abstract] [Full Text] [PDF]