De-ubiquitinating Enzyme A20Block HIV-1Gene Transcription Cooperatively Activitated By HMBA And Prostratin

A critical obstacle in the management of ADIS is HIV latency, that is the host cells latently infected with HIV are not eliminated by antiviral drugs. One strategy to eliminated latently infected cells is to activate the latent HIV in presence of anti-viral drugs, so that the infected cells might be eliminated by viral toxicity or by the host’s immune system. Previous studies showed that the HIV latent state is due to suppression of transcription. In this article, we find that the combination drug treatment with HMBA and Prostratin can greatly activate the transcription of the HIV-1gene. We further studied the molecular mechanism for the promotion of HIV-1transcription. In our study, we demonstrate that HMBA and Prostratin can cooperatively down-regulate the de-ubiquitinating enzyme A20,which is a negative regulating molecular in NF-κ B signaling pathway. With A20down-regulated, HMBA and Prostratin could maintain the NF-κ B signaling pathway continuously active, which brings two consequences. On the one hand, NF-kκ B, as a transcriptional regulating factor, accumulates onto the promoter of HIV-1and stimulating the initiation of HIV-1transcription. On the other hand, HMBA and Prostratin promote the long-term interaction of p65and Brd4. Published studies indicated that Brd4plays a role as a recruiter for p-TEFb (positive transcription elongation factor b) by binding to NF-κ B. Taken together, we suggest that HMBA and Prostratin promote association between p65and Brd4and thereby stimulating transcription elongation of HIV-1. Although the mechanism of how these two drugs down-regulate A20expression remains to be investigated, here we reveal the molecular mechanism of the two drugs on the activation of HIV-1gene expression, which may be applied to activate HIV from latency for its elimination.