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J Biol Chem. 2019 Jan 4;294(1):116-129. doi: 10.1074/jbc.RA118.005798. Epub 2018 Nov 9.

Benzolactam-related compounds promote apoptosis of HIV-infected human cells via protein kinase C-induced HIV latency reversal.

Author information

1
From the National Center for Global Health and Medicine Research Institute, Tokyo 162-8655, Japan.
2
the Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan.
3
the AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
4
the AIDS Research Centre, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
5
the Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.
6
the Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan, and.
7
the Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892-1868.
8
From the National Center for Global Health and Medicine Research Institute, Tokyo 162-8655, Japan, kmaeda@ri.ncgm.go.jp.

Abstract

Latency-reversing agents (LRAs) are considered a potential strategy for curing cells of HIV-1 infection. Certain protein kinase C (PKC) activators have been previously reported to be LRAs because they can reverse HIV latency. In the present study, we examined the activities of a panel of benzolactam derivatives against cells latently infected with HIV. Using determination of p24 antigen in cell supernatants or altered intracellular GFP expression to measure HIV reactivation from latently infected cells along with a cytotoxicity assay, we found that some of the compounds exhibited latency-reversing activity, which was followed by enhanced release of HIV particles from the cells. One derivative, BL-V8-310, displayed activity in ACH-2 and J-Lat cells latently infected with HIV at a concentration of 10 nm or higher, which was superior to the activity of another highly active PKC activator, prostratin. These results were confirmed with peripheral blood cells from HIV-infected patients. We also found that these drugs up-regulate the expression of caspase 3 and enhance apoptosis specifically in latently HIV-infected cells. Moreover, combining BL-V8-310 with a bromodomain-containing 4 (BRD4) inhibitor, JQ1, not only enhanced HIV latency-reversing activity, but also reduced the effect on cytotoxic cytokine secretion from CD4+ T-cells induced by BL-V8-310 alone. Our results suggest that BL-V8-310 and its related benzolactam derivatives are potential LRA lead compounds that are effective in reversing HIV latency and reducing viral reservoirs in HIV-positive individuals with few adverse effects.

KEYWORDS:

HIV cure; PKC activator; antiviral agent; apoptosis; benzolactam; human immunodeficiency virus (HIV); latency-reversing agents; latent infection; protein kinase C (PKC); retrovirus

PMID:
30413535
PMCID:
PMC6322896
DOI:
10.1074/jbc.RA118.005798
[Indexed for MEDLINE]
Free PMC Article

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