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Copyright © 2008 Wu et al; licensee BioMed Central Ltd. Drug 9AA reactivates p21/Waf1 and Inhibits HIV-1 progeny formation Weilin Wu,1 Kylene Kehn-Hall,1 Caitlin Pedati,1 Lynnsey Zweier,1 Iris Castro,1 Zachary Klase,1 Cynthia S Dowd,2 Larisa Dubrovsky,1 Michael Bukrinsky,1 and Fatah Kashanchi  1,3,41The George Washington University Medical Center, Department of Biochemistry and Molecular Biology, Washington, DC 20037, USA 2The George Washington University, Department of ChemistryWashington, DC 20037, USA 3The Institute for Genomic Research, Rockville, MD 20850, USA 4The George Washington University, W.M. Keck Institute for Proteomics Technology and Applications, Washington, DC 20037, USA Corresponding author.Weilin Wu: bcmwxw/at/gwumc.edu; Kylene Kehn-Hall: bcmkwk/at/gwumc.edu; Caitlin Pedati: bcmcsp/at/gwumc.edu; Lynnsey Zweier: analaz/at/gwumc.edu; Iris Castro: analaz/at/gwumc.edu; Zachary Klase: bcmzak/at/gwumc.edu; Cynthia S Dowd: cdowd/at/gwu.edu; Larisa Dubrovsky: mtmsxd/at/gwumc.edu; Michael Bukrinsky: mtmmib/at/gwumc.edu; Fatah Kashanchi: bcmfxk/at/gwumc.edu Received January 30, 2008; Accepted March 18, 2008. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | ||||
Abstract It has been demonstrated that the p53 pathway plays an important role in HIV-1 infection. Previous work from our lab has established a model demonstrating how p53 could become inactivated in HIV-1 infected cells through binding to Tat. Subsequently, p53 was inactivated and lost its ability to transactivate its downstream target gene p21/waf1. P21/waf1 is a well-known cdk inhibitor (CKI) that can lead to cell cycle arrest upon DNA damage. Most recently, the p21/waf1 function was further investigated as a molecular barrier for HIV-1 infection of stem cells. Therefore, we reason that the restoration of the p53 and p21/waf1 pathways could be a possible theraputical arsenal for combating HIV-1 infection. In this current study, we show that a small chemical molecule, 9-aminoacridine (9AA) at low concentrations, could efficiently reactivate p53 pathway and thereby restoring the p21/waf1 function. Further, we show that the 9AA could significantly inhibit virus replication in activated PBMCs, likely through a mechanism of inhibiting the viral replication machinery. A mechanism study reveals that the phosphorylated p53ser15 may be dissociated from binding to HIV-1 Tat protein, thereby activating the p21/waf1 gene. Finally, we also show that the 9AA-activated p21/waf1 is recruited to HIV-1 preintegration complex, through a mechanism yet to be elucidated. | ||||
