Abstract
BackgroundHIV-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.ResultsWe 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.ConclusionsThese studies provide evidence that PKC412 is a new compound with the potential for optimization as a latency-reactivator to eradicate HIV-1 infection.
Highlights
HIV-1 latency is a major obstacle for HIV-1 eradication
Consistent with previous studies showing that PKC412 exhibited broad antiproliferative activity against various tumor and normal cell lines [48, 49], a proliferation inhibition effect of PKC412 was observed in proliferating ACH2 cells with a CCID50 of 0.4 μM (Fig. 1d and data not shown)
Because DNA methylation has been proposed as a vital transcription restriction factor that contributes to the maintenance of HIV latency and the promoter region in the 5′long terminal repeat (LTR) of HIV-1 is epigenetically regulated by DNA methylation [12, 14, 57], we investigated the level of CpG methylation in the HIV-1 5’LTR after PKC412
Summary
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. HIV latency has been defined as a reversibly nonproductive state of infection of individual cells that retain the capacity to produce infectious virus particles but allow the virus to evade the host immune response [1]. Several mechanisms can silence HIV gene expression and replication in HIV-1 latently infected resting CD4 + T cells, especially transcriptional interference and the chromatin environment. HIV latency is the major barrier to an HIV-1 cure. Extensive research efforts have been focused on finding ways to reactivate HIV-1 latent reservoirs and
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