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

Weilin Wu1, Kylene Kehn-Hall, Caitlin Pedati

  • 1The George Washington University Medical Center, Department of Biochemistry and Molecular Biology, Washington, DC 20037, USA. bcmwxw@gwumc.edu

Virology Journal
|March 20, 2008
PubMed

Insights

Restoring the p53 and p21/waf1 pathways with 9-aminoacridine (9AA) inhibits HIV-1 replication. This small molecule reactivates p53, restoring p21/waf1 function and blocking viral spread.

Area of Science:

  • Virology
  • Molecular Biology
  • Cellular Biology

Background:

  • The p53 pathway is crucial in HIV-1 infection, with p53 inactivation by HIV-1 Tat impairing p21/waf1 gene expression.
  • p21/waf1, a cyclin-dependent kinase inhibitor (CKI), functions as a molecular barrier against HIV-1 in stem cells.

Purpose of the Study:

  • To investigate the potential of restoring p53 and p21/waf1 pathways as a therapeutic strategy against HIV-1 infection.
  • To evaluate the efficacy of 9-aminoacridine (9AA) in reactivating these pathways and inhibiting viral replication.

Main Methods:

  • Treatment of activated peripheral blood mononuclear cells (PBMCs) with 9-aminoacridine (9AA).
  • Assays to measure p53 pathway activation, p21/waf1 restoration, and HIV-1 replication.
  • Mechanistic studies involving phosphorylated p53ser15, HIV-1 Tat binding, and p21/waf1 recruitment to the preintegration complex.

Main Results:

  • Low concentrations of 9AA efficiently reactivated the p53 pathway, restoring p21/waf1 function.
  • 9AA significantly inhibited HIV-1 replication in activated PBMCs, likely by targeting the viral replication machinery.
  • Phosphorylated p53ser15 dissociation from HIV-1 Tat was observed, leading to p21/waf1 gene activation.

Conclusions:

  • 9-aminoacridine (9AA) shows therapeutic potential for combating HIV-1 by reactivating the p53/p21/waf1 axis.
  • The study elucidates a mechanism involving 9AA-mediated p53 reactivation and subsequent inhibition of HIV-1 replication.
  • Further research is needed to fully understand the recruitment of 9AA-activated p21/waf1 to the HIV-1 preintegration complex.

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