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Virol J. 2016 Oct 21;13(1):177.

Activation of HIV-1 expression in latently infected CD4+ T cells by the small molecule PKC412.

Author information

1
Department of Microbiology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, 410078, People's Republic of China.
2
Laboratory of Molecular Human Retrovirology, Department of Medical Microbiology, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada.
3
Laboratory of Molecular Human Retrovirology, Department of Medical Microbiology, Rady Faculty of Medicine, University of Manitoba, Winnipeg, MB, Canada. xiao-jian.yao@umanitoba.ca.

Abstract

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.

KEYWORDS:

ACH2 cells; HIV latency; NF-κB signaling; PKC412; Resting CD4+ T cells

PMID:
27769267
PMCID:
PMC5073835
DOI:
10.1186/s12985-016-0637-9
[Indexed for MEDLINE]
Free PMC Article

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