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Prostratin antagonizes HIV latency by activating NF-kappaB
Samuel A Williams1, Lin-Feng Chen, Hakju Kwon
1Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, California 94141, USA.
The Journal of Biological Chemistry
|July 31, 2004
Summary
Prostratin effectively activates latent human immunodeficiency virus (HIV) gene expression by targeting the NF-kappaB pathway. This finding offers a potential strategy to sensitize HIV-infected cells to antiretroviral therapy.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Latent human immunodeficiency virus (HIV) reservoirs in CD4 T cells are a major obstacle to viral eradication.
- Activating latent HIV may sensitize cells to antiretroviral therapy.
Purpose of the Study:
- To investigate prostratin's efficacy in activating latent HIV gene expression.
- To elucidate the molecular mechanisms underlying prostratin-mediated HIV activation.
Main Methods:
- Utilized J-Lat Jurkat T cell lines harboring latent HIV proviruses.
- Assessed HIV gene expression and NF-kappaB pathway activation.
- Employed chromatin immunoprecipitation assays and protein kinase C (PKC) isoform inhibition.
Main Results:
- Prostratin effectively activated HIV gene expression in J-Lat cells.
- Activation involved IKK-dependent degradation of IkappaBalpha, leading to NF-kappaB nuclear translocation.
- Prostratin induced RelA binding to the HIV-1 long terminal repeat and stimulated PKC isoforms, particularly novel PKCs.
Conclusions:
- Prostratin is a potent activator of latent HIV gene expression.
- The mechanism involves NF-kappaB pathway activation, with a significant role for novel protein kinase C isoforms.
- These findings provide insights into targeting HIV latency.