Departments of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, California, United States of America.
PLoS One. 2018 Nov 26;13(11):e0208055. doi: 10.1371/journal.pone.0208055. eCollection 2018.
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.
虽然抗逆转录病毒疗法大大延长了 HIV 感染者的生命，但目前的治疗方法无法完全清除病毒感染的细胞。已经提出了许多潜伏逆转剂，用于“震撼和杀伤”策略，以重新激活潜伏的 HIV，从而使其容易受到杀伤机制的影响。原花青素三聚体 C1（PC1）是一种在多种植物来源中发现的类黄酮，包括葡萄、苹果和可可，具有抗氧化和抗炎特性。我们确定 PC1 通过激活 MAPK 途径重新激活细胞系和 HIV 原代细胞模型中的潜伏 HIV。值得注意的是，PC1 重新激活潜伏 HIV 而不会增加 T 细胞激活的表面标志物。通过不同机制激活 HIV 转录的几种治疗方法是临床重新激活潜伏储库的最有效方法。我们在细胞系和 HIV 潜伏原代细胞模型中使用 PC1（MAPK 激动剂）、甘遂（PKC 激动剂）和 JQ1（BET 溴结构域抑制剂）的三联组合方法重新激活潜伏 HIV。当联合使用时，即使作为单一治疗方法也无法重新激活 HIV 的低浓度也有效。因此，几种使用不同激活途径的机制共同作用以重新激活潜伏的 HIV。
