Prostratin antagonizes HIV latency by activating NF-kappaB.

Published

Journal Article

A subset of quiescent memory CD4 T cells harboring integrated but transcriptionally silent proviruses poses a currently insurmountable barrier to the eradication of the human immunodeficiency virus (HIV) in infected patients. Induction of HIV gene expression in these latently infected cells by immune activating agents has been proposed as one approach to confer sensitivity to antiretroviral therapy. Interest has recently focused on the non-tumor-promoting phorbol ester, prostratin, as a potential agent to activate latent HIV proviruses. Using multiple Jurkat T cell lines containing integrated but transcriptionally latent HIV proviruses (J-Lat cells), we now demonstrate that prostratin effectively activates HIV gene expression in these latently infected cells. We further show that prostratin acts by stimulating IKK-dependent phosphorylation and degradation of IkappaBalpha, leading to the rapid nuclear translocation of NF-kappaB and activation of the HIV-1 long terminal repeat in a kappaB enhancer-dependent manner. In contrast, NFAT and AP-1 are not induced by prostratin. Using chromatin immunoprecipitation assays to identify host transcription factors recruited to the latent HIV-1 promoter in living cells, we find that prostratin induces RelA binding. Analysis of potential upstream signal transducers demonstrates that prostratin stimulates membrane translocation of classical, novel, and atypical protein kinase C (PKC) isoforms. Studies with isoform-specific PKC inhibitors suggest that the novel PKCs play a particularly prominent role in the prostratin response. These findings provide new insights into the molecular pathway through which prostratin antagonizes HIV latency highlighting a central role for the action of NF-kappaB.

Full Text

Cited Authors

  • Williams, SA; Chen, L-F; Kwon, H; Fenard, D; Bisgrove, D; Verdin, E; Greene, WC

Published Date

  • October 2004

Published In

Volume / Issue

  • 279 / 40

Start / End Page

  • 42008 - 42017

PubMed ID

  • 15284245

Pubmed Central ID

  • 15284245

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.m402124200

Language

  • eng