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Assessing the Innate Sensing of HIV-1 Infected CD4+ T Cells by Plasmacytoid Dendritic Cells Using an Ex vivo Co-culture System.
Published on: September 1, 2015
Activation of HIV-1 expression in latently infected CD4+ T cells by the small molecule PKC412
Zhujun Ao1,2, Rong Zhu2, Xiaoli Tan1
1Department of Microbiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410078, People's Republic of China.
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.
Insights
A novel kinase inhibitor, PKC412 (midostaurin), effectively reactivates latent HIV-1. Combining it with other drugs shows additive effects, offering a new strategy for HIV eradication.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- HIV-1 latency presents a significant barrier to eradicating the virus.
- Reactivating latent HIV reservoirs is crucial for eliminating infected cells.
Purpose of the Study:
- To identify small molecules capable of reactivating latent HIV-1.
- To evaluate the potential of PKC412 (midostaurin) as an HIV-1 latency-reversing agent.
Main Methods:
- Screening of over 1,500 small molecules and kinase inhibitors.
- Testing PKC412 in the HIV-1 latently infected ACH2 cell line and primary CD4+ T cells.
- Assessing the additive effects of PKC412 combined with vorinostat (HDAC inhibitor).
Main Results:
- PKC412 (midostaurin) demonstrated dose- and time-dependent reactivation of HIV-1 expression.
- Nuclear factor κB (NF-κB) signaling is implicated in PKC412-mediated HIV-1 activation.
- Combination therapy with PKC412 and vorinostat showed additive effects on HIV-1 reactivation.
Conclusions:
- PKC412 is a promising compound for reactivating latent HIV-1.
- Further optimization of PKC412 could lead to novel strategies for HIV-1 eradication.
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