Discovering the Mechanisms of Wikstroelide E as a Potential HIV-Latency-Reversing Agent by Transcriptome Profiling

The discovery of efficient and specific HIV-latency-reversing agents is critical for HIV therapy. Here, we developed wikstroelide E, a daphnane diterpene from the buds of Wikstroemia chamaedaphne, as a potential HIV-latency-reversing agent that is 2500-fold more potent than the drug prostratin. Based on transcriptome analysis, the underlying mechanism was that wikstroelide E regulated the MAPK, PI3K-Akt, JAK-Stat, TNF, and NF-kappa B signaling pathways. We clearly demonstrated that wikstroelide E reversed latent HIV infection by activating PKC-NF-kappa B signals, serving as a proxy for verifying the transcriptome data. Strikingly, the Tat protein contributes to the robust activation of latent HIV in wikstroelide-E-treated cells, producing an unexpected latency-reversing effect against latent HIV. This study provides the basis for the potential development of wikstroelide E as an effective HIV-latency-reversing agent.

高效且特异的艾滋病病毒（HIV）潜伏逆转剂的发现对HIV治疗至关重要。在此，我们开发了西瑞香素E，它是一种从河朔荛花的芽中提取的瑞香烷型二萜，是一种潜在的HIV潜伏逆转剂，其效力比药物普罗司他丁高2500倍。基于转录组分析，其潜在机制是西瑞香素E调节丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇-3激酶 - 蛋白激酶B（PI3K - Akt）、 Janus激酶 - 信号转导及转录激活因子（JAK - Stat）、肿瘤坏死因子（TNF）和核因子κB（NF - κB）信号通路。我们明确证明西瑞香素E通过激活蛋白激酶C - 核因子κB（PKC - NF - κB）信号逆转潜伏的HIV感染，以此作为验证转录组数据的一个参照。引人注目的是，Tat蛋白有助于在西瑞香素E处理的细胞中强烈激活潜伏的HIV，对潜伏的HIV产生意想不到的潜伏逆转效果。这项研究为西瑞香素E作为一种有效的HIV潜伏逆转剂的潜在开发提供了依据。