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

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

  • J Biol Chem. 2019 Jan 4;294(1):116-129. doi: 10.1074/jbc.RA118.005798.
Kouki Matsuda 1,  Takuya Kobayakawa 2,  Kiyoto Tsuchiya 3,  Shin-Ichiro Hattori 1,  Wataru Nomura 2,  Hiroyuki Gatanaga 3,  Kazuhisa Yoshimura 4,  Shinichi Oka 3,  Yasuyuki Endo 5,  Hirokazu Tamamura 2,  Hiroaki Mitsuya 6,  Kenji Maeda 7
Affiliations

Affiliations

  • 1 National Center for Global Health and Medicine Research Institute, Tokyo 162-8655, Japan.
  • 2 Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, 101-0062, Japan.
  • 3 AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
  • 4 AIDS Research Centre, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan.
  • 5 Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan.
  • 6 National Center for Global Health and Medicine Research Institute, Tokyo 162-8655, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892-1868.
  • 7 National Center for Global Health and Medicine Research Institute, Tokyo 162-8655, Japan. Electronic address: kmaeda@ri.ncgm.go.jp.
PMID: 30413535 DOI: 10.1074/jbc.RA118.005798
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.

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