Figure 3.

Transcriptional reactivation of HIV-1 LTR by stimulation/activation of initiation and elongation factors. Several compounds including T cell activators and differentiating agents have been identified that induce transcription of latent HIV-1 integrated genome. These act as inducers of protein PKC and NF-κB/NF-AT pathways and P-TEFb stimulators. Briostatin-1 and Prostratin are activators of PKC that once activated, phosphorylates the NF-κB-inhibitor IκB-α with its subsequent degradation and accumulation in the nucleus of the active NF-κB (RelA/p50) heterodimer. Activated PKC also triggers the MAP kinase pathway activating the AP1 dimeric factor (Fos/Jun) also recruited to the LTR enhancer upon binding to NF-κB. AV6 requires activation of NFAT to stimulate reactivation. HMBA activates the calcium pathway and calcineurin, contributing to NFAT activation, and stimulates the AKT kinase, which in turn phosphorylates HEXIM1, with the release of the P-TEFb (CycT1 and CDK-9) elongation factor from the inhibitory complex (HEXIM1/7SKsnRNP). Disulfiram stimulates the degradation of PTEN, similarly determining the activation of AKT and the release of HEXIM1. JQ1, by targeting BRD4, may release P-TEFb, promoting elongation.