A Therapeutic Strategy to Combat HIV-1 Latently Infected Cells With a Combination of Latency-Reversing Agents Containing DAG-Lactone PKC Activators

Kouki Matsuda; Takuya Kobayakawa; Ryusho Kariya; Kiyoto Tsuchiya; Shoraku Ryu; Kohei Tsuji; Takahiro Ishii; Hiroyuki Gatanaga; Kazuhisa Yoshimura; Seiji Okada; Akinobu Hamada; Hiroaki Mitsuya; Hirokazu Tamamura; Kenji Maeda

doi:10.3389/fmicb.2021.636276

A Therapeutic Strategy to Combat HIV-1 Latently Infected Cells With a Combination of Latency-Reversing Agents Containing DAG-Lactone PKC Activators

Front Microbiol. 2021 Mar 17:12:636276. doi: 10.3389/fmicb.2021.636276. eCollection 2021.

Authors

Affiliations

¹ National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
² Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Bunkyō, Japan.
³ Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan.
⁴ AIDS Clinical Center, National Center for Global Health and Medicine, Shinjuku, Japan.
⁵ Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan.
⁶ AIDS Research Centre, National Institute of Infectious Diseases, Tokyo, Japan.
⁷ Tokyo Metropolitan Institute of Public Health, Tokyo, Japan.
⁸ HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

Abstract

Advances in antiviral therapy have dramatically improved the therapeutic effects on HIV type 1 (HIV-1) infection. However, even with potent combined antiretroviral therapy, HIV-1 latently infected cells cannot be fully eradicated. Latency-reversing agents (LRAs) are considered a potential tool for eliminating such cells; however, recent in vitro and in vivo studies have raised serious concerns regarding the efficacy and safety of the "shock and kill" strategy using LRAs. In the present study, we examined the activity and safety of a panel of protein kinase C (PKC) activators with a diacylglycerol (DAG)-lactone structure that mimics DAG, an endogenous ligand for PKC isozymes. YSE028, a DAG-lactone derivative, reversed HIV-1 latency in vitro when tested using HIV-1 latently infected cells (e.g., ACH2 and J-Lat cells) and primary cells from HIV-1-infected individuals. The activity of YSE028 in reversing HIV-1 latency was synergistically enhanced when combined with JQ1, a bromodomain and extra-terminal inhibitor LRA. DAG-lactone PKC activators also induced caspase-mediated apoptosis, specifically in HIV-1 latently infected cells. In addition, these DAG-lactone PKC activators showed minimal toxicity in vitro and in vivo. These data suggest that DAG-lactone PKC activators may serve as potential candidates for combination therapy against HIV-1 latently infected cells, especially when combined with other LRAs with a different mechanism, to minimize side effects and achieve maximum efficacy in various reservoir cells of the whole body.

Keywords: HIV-1; HIV-1 latently infected cells; HIV-1 reservoirs; diacylglycerol-lactone; protein kinase C activator.