Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART

Abstract

Prostratin is a unique phorbol ester that stimulates protein kinase C activity but is nontumor promoting. Remarkably, prostratin is also able to inhibit de novo human immunodeficiency virus type 1 (HIV-1) infection yet up-regulate viral expression from latent proviruses. Prostratin's lack of tumor promotion, coupled with its ability to block viral spread yet induce latent proviral expression, prompted studies to determine whether this compound could serve as an inductive adjuvant therapy for patients treated with highly active antiretroviral therapy (HAART).

Prostratin Antagonizes HIV Latency by Activating NF-κB

“…We find that prostratin effectively activates the latent provirus in multiple independently derived J-Lat T-cell clones. These results are in agreement with recently published results demonstrating prostratin-mediated activation of latent virus in the SCID-HU Thy/Liv system and in the blood of patients with HAART-suppressed HIV (14,15). We observed that prostratin induces similar levels of proviral gene transcription as TNF-␣, although the kinetics of the prostratin-mediated response are slower.…”

“…Considerable interest has recently focused on prostratin as an in vivo agent to purge latent HIV proviruses (6,14,15). As a cellular model of HIV latency, we employed the J-Lat T cells, which contain a full-length latent HIV provirus.…”

“…Recent interest has focused on prostratin, a nontumorigenic phorbol ester, as a potential antagonist of HIV latency (14,15).…”

“…Early studies of prostratin demonstrated that this agent inhibits HIV replication in vitro at micromolar concentrations via down-regulation of the cellular HIV receptors CD4 and CXCR4 (14,18). More recent studies have shown that prostratin also promotes transcriptional activation of latent HIV proviruses in latently infected thymocytes present in the SCID-hu Thy/Liv model (15).…”

Progress and challenges in the use of latent HIV-1 reactivating agents

“…In addition, prostratin elicits pleiotropic effects relevant to HIV treatment. It causes downregulation of CD4, CXCR4 and, in some cases, CCR5 and thereby protects CD4 + T cells from infection [61,62] . Further investigation revealed that prostratin induces PKC-mediated phosphorylation, and the degradation of IκB and enables the subsequent release and penetration of transcriptional factor NF-κB into the cell nucleus, where NF-κB binds to LTRs, leading to transcriptional initiation [63] .…”