15-Deoxy-Δ12,14-prostaglandin J2 inhibits HIV-1 transactivating protein, Tat, through covalent modification

Parisa Kalantari, Vivek Narayan, Andrew J. Henderson, K. Sandeep Prabhu

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Controlling the HIV/AIDS epidemic remains a major challenge, with approximately 5 million new HIV infections annually. Cyclopentenone prostaglandins (CyPG), such as 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), are arachidonic acid-derived endogenous electrophiles that possess anti-HIV activity by an unknown mechanism. Given that the reactive α,β-unsaturated ketone in the cyclopentenone ring of 15d-PGJ 2 covalently modifies key Cys thiols in select proteins, we hypothesized that 15d-PGJ2 inhibits HIV transcription and replication by targeting Cys thiols in HIV-1 Tat. Tat is a potent transactivator of viral gene expression required for HIV transcriptional elongation and replication. Our studies indicate that 15d-PGJ2 treatment of cells inhibits Tat-dependent transcription and replication of HIV-1, while 9,10-dihydro-15d- PGJ2, PGE2, PGF, or PGD2 that lack the reactive α,β-unsaturated ketone were ineffective. The inhibition of Tat activity by 15d-PGJ2 was dose-dependent, with an IC50 of 1.2 μM and independent of NF-κB pathway. Furthermore, using a biotinylated derivative of 15d-PGJ2, we demonstrate that 15d-PGJ2 modifies free Cys-thiols in Tat to form covalent Michael adducts and that the interaction was further increased on reduction of Tat. 15d-PGJ2-modified Tat was unable to transactivate the HIV long terminal repeat in U937 human macrophages. These data demonstrate that Tat acts as a molecular target of CyPG leading to the inhibition of transcription and also suggest a novel therapeutic approach to complement current antiretroviral strategies for HIV/AIDS.

Original languageEnglish (US)
Pages (from-to)2366-2373
Number of pages8
JournalFASEB Journal
Volume23
Issue number8
DOIs
StatePublished - Aug 1 2009

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All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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