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* Laboratory of Neurotoxicology,
Department of Pharmacology and Experimental Neuroscience, and
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198;
Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; and
¶ The China-U.S. Joint Research Center for Life Sciences, Beijing, China
Macrophages serve as a major reservoir for HIV-1 because a large number of macrophages in the brain and lung are infected with HIV-1 during late stage disease. Recent evidence suggests that those HIV-1-infected macrophages play a key role in contributing to tissue damage in AIDS pathogenesis. Macrophages undergo apoptosis upon HIV-1 infection; however, the mechanisms of this process are not well-defined. Previously, we demonstrated that HIV-1 infection inhibits Akt-1, a critical protein for cell survival of macrophages. In the present study, we investigated the involvement of transcription factor FOXO3a in the regulation of HIV-1-mediated apoptosis in macrophages. HIV-1 infection significantly decreased phosphorylation of FOXO3a and promoted FOXO3a translocation to the nucleus in human monocyte-derived macrophages (MDM). Overexpression of a constitutively active FOXO3a increased DNA fragmentation with decreased cell viability in MDM, whereas a dominant-negative mutant of FOXO3a or small interfering RNA for FOXO3a to knockdown the function of FOXO3a in HIV-1-infected MDM decreased DNA fragmentation and protected macrophages from death in HIV-1-infected MDM. Overexpression of constitutively active Akt-1 increased FOXO3a phosphorylation, suggesting that FOXO3a phosphorylation in human MDM is dependent on Akt-1. We therefore conclude that FOXO3a plays an important role in HIV-1-induced cell death of human macrophage. Understanding the PI3K/Akt-1/FOXO3a pathway and its associated death mechanism in macrophages during HIV-1 infection would lead to identification of potential therapeutic avenues for the treatment of HIV-1 infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Research Grants R01 NS 41858, P20 RR15635, and P01 NS043985 (to J.Z.).
2 M.C. performed this research project at the University of Nebraska Medical Center while she was a visiting PhD student from the Chinese Academy of Sciences.
3 M.C. and Y.H. contributed equally to this work.
4 Address correspondence and reprint requests to Dr. Jialin Zheng, University of Nebraska Medical Center, Omaha, NE 68198-5880. E-mail address: jzheng{at}unmc.edu or Dr. Yong Zhao, Institute of Zoology, Chinese Academy of Sciences, Datun Road Yi 5, Beijing, 100101, China. E-mail address: zhaoy{at}ioz.ac.cn
5 Abbreviations used in this paper: MDM, monocyte-derived macrophage; AZT, azidothymidine; DN, dominant negative; MOI, multiplicity of infection; RT, reverse transcription; TBP, TATA box binding protein; PI, propidium iodide; siRNA, small interfering RNA.
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  M. Noursadeghi, J. Tsang, R. F. Miller, and D. R. Katz Comment on "Transcription Factor FOXO3a Mediates Apoptosis in HIV-1-Infected Macrophages" J. Immunol., June 15, 2008; 180(12): 7783 - 7783. [Full Text] [PDF]
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Y. Huang, M. Cui, N. Erdmann, A. A. Constantino, Y. Zhao, and J. Zheng Response to Comment on "Transcription Factor FOXO3a Mediates Apoptosis in HIV-1-Infected Macrophages" J. Immunol., June 15, 2008; 180(12): 7783 - 7784. [Full Text] [PDF]
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