1. Academic Validation
  2. Elimination of HIV-1 Latently Infected Cells by Gnidimacrin and a Selective HDAC Inhibitor

Elimination of HIV-1 Latently Infected Cells by Gnidimacrin and a Selective HDAC Inhibitor

  • ACS Med Chem Lett. 2018 Feb 6;9(3):268-273. doi: 10.1021/acsmedchemlett.8b00012.
Li Huang 1 Wei-Hong Lai 1 Lei Zhu 1 Wei Li 2 Lei Wei 3 Kuo-Hsiung Lee 4 5 Lan Xie 3 Chin-Ho Chen 1
Affiliations

Affiliations

  • 1 Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, United States.
  • 2 Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
  • 3 Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
  • 4 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
  • 5 Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan.
Abstract

We have previously reported gnidimacrin (GM), a protein kinase C (PKC) agonist, significantly reduces the frequency of HIV-1 latently infected cells in peripheral blood mononuclear cells (PBMCs) from patients undergoing successful antiretroviral therapy at low picomolar concentrations ex vivo, which is distinct from other latency reversing agents. In this study, we demonstrate that strong viral reactivation by GM is a mechanism for elimination of latently infected cells, and a histone deacetylase inhibitor (HDACI), a thiophenyl benzamide (TPB), further potentiated the efficacy of GM against latent HIV-1. The effect of GM on latent HIV-1 activation was potentiated by TPB in cell models by 2-3-fold. The GM/TPB combination further decreased the frequency of HIV-infected cells in latently infected patient PBMCs over 3-fold when compared with GM alone, which caused a 5-fold reduction compared with the solvent control. Thus, GM/TPB is a unique combination that may reduce latent HIV-1 reservoirs at nontoxic concentrations.

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