Activation of HIV-1 expression in latently infected CD4+ T cells by the small molecule PKC412.
BACKGROUND
HIV-1 latency is a major obstacle for HIV-1 eradication. Extensive efforts are being directed toward the reactivation of latent HIV reservoirs with the aim of eliminating latently infected cells via the host immune system and/or virus-mediated cell lysis.


RESULTS
We screened over 1,500 small molecules and kinase inhibitors and found that a small molecule, PKC412 (midostaurin, a broad-spectrum kinase inhibitor), can stimulate viral transcription and expression from the HIV-1 latently infected ACH2 cell line and primary resting CD4+ T cells. PKC412 reactivated HIV-1 expression in ACH2 cells in a dose- and time-dependent manner. Our results also suggest that the nuclear factor κB (NF-κB) signaling could be one of cellular pathways activated during PKC412-mediated activation of latent HIV-1 expression. Additionally, combining PKC412 with the HDAC inhibitor vorinostat (VOR) had an additive effect on HIV-1 reactivation in both ACH2 cells and infected resting CD4+ T cells.


CONCLUSIONS
These studies provide evidence that PKC412 is a new compound with the potential for optimization as a latency-reactivator to eradicate HIV-1 infection.
['Ao|Zhujun|Z|', 'Zhu|Rong|R|', 'Tan|Xiaoli|X|', 'Liu|Lisa|L|', 'Chen|Liyu|L|', 'Liu|Shuiping|S|', 'Yao|XiaoJian|X|']
D015496:CD4-Positive T-Lymphocytes D004353:Drug Evaluation, Preclinical D015497:HIV-1 D006801:Humans D047428:Protein Kinase Inhibitors D019311:Staurosporine D014775:Virus Activation D017735:Virus Latency
PKC412 ACH2 cells Resting CD4+ T cells HIV latency NF-κB signaling