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15-Deoxy-Δ12,14-prostaglandin J2 inhibits HIV-1 transactivating protein, Tat, through covalent modification.
- Source :
-
FASEB Journal . Aug2009, Vol. 23 Issue 8, p2366-2373. 8p. 6 Graphs. - Publication Year :
- 2009
-
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-PGJ2 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, PGF2α, 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 surest a novel therapeutic approach to complement current antiretroviral strategies for HIV/AIDS. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 08926638
- Volume :
- 23
- Issue :
- 8
- Database :
- Academic Search Index
- Journal :
- FASEB Journal
- Publication Type :
- Academic Journal
- Accession number :
- 44226765
- Full Text :
- https://doi.org/10.1096/fj.08-124982