Procyanidin trimer C1 reactivates latent HIV as a triple combination therapy with kansui and JQ1

• Published in: PloS one 2018-11, Vol.13 (11), p.e0208055
• Main Authors: Cary, Daniele C, Peterlin, B Matija
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Anti-HIV Agents - pharmacology; Anti-inflammatory agents; Antioxidants; Antioxidants (Nutrients); Antiretroviral agents; Azepines - pharmacology; Biology and Life Sciences; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - enzymology; CD4-Positive T-Lymphocytes - virology; Cell activation; Cell culture; Cell cycle; Cell Line; Cell surface; Combination therapy; Dosage and administration; Dose-Response Relationship, Drug; Drug resistance; Drug Synergism; Drug therapy; Drug Therapy, Combination; Enzyme Inhibitors - pharmacology; Flavonoids; Flavonoids - pharmacology; Gene expression; HIV; HIV infections; HIV Infections - drug therapy; HIV Infections - enzymology; HIV Infections - virology; HIV patients; HIV-1 - drug effects; HIV-1 - physiology; Human immunodeficiency virus; Humans; Immunology; Inflammation; Jurkat Cells; Kinases; Latency; Low concentrations; Lymphocytes; Lymphocytes T; MAP kinase; Medicine; Medicine and Health Sciences; Polyphenols; Primary Cell Culture; Procyanidins; Procyclidine; Protein kinase C; Proteins; Research and Analysis Methods; RNA polymerase; Shock; Surface markers; T cells; Therapeutics; Transcription; Triazoles - pharmacology; Trimers; Virus Latency - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0208055

Although anti-retroviral therapies have greatly extended the lives of HIV infected individuals, current treatments are unable to completely eliminate virally infected cells. A number of latency reversing agents have been proposed for use in a "shock and kill" strategy to reactivate latent HIV, thus making it vulnerable to killing mechanisms. Procyanidin trimer C1 (PC1) is a flavonoid found in multiple plant sources including grape, apple, and cacao, which has antioxidant and anti-inflammatory properties. We determined that PC1 reactivates latent HIV in cell line and primary cell models of HIV, through activation of the MAPK pathway. Notably, PC1 reactivates latent HIV without increasing surface markers of T cell activation. Combining several therapeutics, which activate HIV transcription through different mechanisms, is the most efficient approach to clinically reactivate latent reservoirs. We utilized PC1 (MAPK agonist), kansui (PKC agonist), and JQ1 (BET bromodomain inhibitor) in a triple combination approach to reactivate latent HIV in cell line and primary cell models of HIV latency. When used in combination, low concentrations which fail to reactivate HIV as single treatments, are effective. Thus, several mechanisms, using distinct activation pathways, act together to reactivate latent HIV.