Drug 9AA reactivates p21/Waf1 and Inhibits HIV-1 progeny formation.
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.
Wu
Weilin
W
The George Washington University Medical Center, Department of Biochemistry and Molecular Biology, Washington, DC 20037, USA. bcmwxw@gwumc.edu
Kehn-Hall
Kylene
K
Pedati
Caitlin
C
Zweier
Lynnsey
L
Castro
Iris
I
Klase
Zachary
Z
Dowd
Cynthia S
CS
Dubrovsky
Larisa
L
Bukrinsky
Michael
M
Kashanchi
Fatah
F
D000585:Aminacrine / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D010766:Phosphorylation; D048348:Reverse Transcription / Q000187:drug effects; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
D000998:Antiviral Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D054322:tat Gene Products, Human Immunodeficiency Virus; D000585:Aminacrine