Drug 9AA reactivates p21/Waf1 and Inhibits HIV-1 progeny formation

Weilin Wu¹ , Kylene Kehn-Hall¹ , Caitlin Pedati¹ , Lynnsey Zweier¹ , Iris Castro¹ , Zachary Klase¹ , Cynthia S Dowd² , Larisa Dubrovsky¹ , Michael Bukrinsky¹ and Fatah Kashanchi¹^,3^,4

¹The 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

author email corresponding author email

Virology Journal 2008, 5:41doi:10.1186/1743-422X-5-41


Published:	18 March 2008

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.