Synthetic Ingenols Maximize Protein Kinase C-Induced HIV-1 Latency Reversal

• Published in: Antimicrobial agents and chemotherapy Vol. 62; no. 11
• Main Authors: Spivak, Adam M, Nell, Racheal A, Petersen, Mark, Martins, Laura, Sebahar, Paul, Looper, Ryan E, Planelles, Vicente
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.11.2018
• Subjects: Antiretroviral Therapy, Highly Active - methods; Antiviral Agents; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Diterpenes; Diterpenes - metabolism; Diterpenes - pharmacology; HIV Infections; HIV Infections - drug therapy; HIV Infections - metabolism; HIV-1; HIV-1 - drug effects; Humans; Jurkat Cells; Protein Kinase C; Protein Kinase C - metabolism; Proviruses - drug effects; Virus Activation - drug effects; Virus Latency; Virus Latency - drug effects; HIV; HIV latency; ingenols; HIV persistence; PKC agonist
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.01361-18

Antiretroviral therapy (ART) does not cure HIV-1 infection due to the persistence of proviruses in long-lived resting T cells. Strategies targeting these latently infected cells will be necessary to eradicate HIV-1 in infected individuals. Protein kinase C (PKC) activation is an effective mechanism to reactivate latent proviruses and allows for recognition and clearance of infected cells by the immune system. Several ingenol compounds, naturally occurring PKC agonists, have been described to have potent latency reversal activity. We sought to optimize this activity by synthesizing a library of novel ingenols via esterification of the C-3 hydroxyl group of the ingenol core, which itself is inactive for latency reversal. Newly synthesized ingenol derivatives were evaluated for latency reversal activity, cellular activation, and cytotoxicity alongside commercially available ingenols (ingenol-3,20-dibenzoate, ingenol 3-hexanoate, and ingenol-3-angelate) in HIV latency cell lines and resting CD4 T cells from aviremic participants. Among the synthetic ingenols that we produced, we identified several compounds that demonstrate high efficacy and represent promising leads as latency reversal agents for HIV-1 eradication.