Combined multi-omics and network pharmacology approach reveals the role of Tripterygium Wilfordii Hook F in treating HIV immunological non-responders.

Xiaosheng Liu, Ling Lin, Tingxia Lv, Lianfeng Lu, Xiaodi Li, Yang Han, Zhifeng Qiu, Xiaoxia Li, Yanling Li, Xiaojing Song, Wei Cao, Taisheng Li

Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology 2022;101():154103

PMID: 35468451

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Abstract

BACKGROUND

The HIV-1 infected immunological non-responders (INRs) are characterized by poor immune reconstitution after long-term treatment. Tripterygium Wilfordii Hook F (TwHF) pill is a traditional Chinese patent drug with extensive immunosuppressive effects and has been clinically proven efficacy in treating INRs.

PURPOSE

The therapeutic mechanism of TwHF pills in the treatment of INRs was investigated by the combined multi-omics analysis on clinical samples and network pharmacology approach.

METHODS

Clinically, the peripheral blood mononuclear cells (PBMC) samples of TwHF-treated INRs from different time points were collected to conduct the transcriptomic and proteomic profiling. Key effector pathways of TwHF were enriched and analyzed by the ingenuity pathway analysis (IPA). Computationally, the TwHF-related compounds were obtained from traditional Chinese medicine databases, and literature search and structural prediction were performed to identify TwHF-related targets. Integrated with the INR-related targets, the 'TwHF-compounds-targets-INR' network was constructed to analyze core effector targets by centrality measurement. Experimentally, the effects of TwHF compounds on the T cells activation and expression of identified targets were evaluated with in vitro cell culture.

RESULTS

33 INRs were included and treated with TwHF pills for 17 (IQR, 12-24) months. These patients experienced rapid growth in the CD4 T cell counts and decreased T cell activation. The multi-omics analysis showed that the interferon (IFN)-signaling pathway was significantly inhibited after taking TwHF pills. The network pharmacology predicted the central role of the signal transducer and activator of transcription 1 (STAT1) in the 'TwHF-compounds-targets-INR' network. Further bioinformatic analysis predicted STAT1 would regulate over 58.8% of identified down-regulated genes. Cell experiments validated that triptolide (TPL) would serve as the major bioactivity compound of TwHF pills to inhibit the immune cell activation, the production of IFN-γ, the expression of downstream IFN-stimulated genes, and the phosphorylation of STAT1.

CONCLUSION

Our research is the first to systemic verify the mechanisms of TwHF in treating INRs. The IFN signaling pathway and the STAT1 would be the major effector targets of TwHF pills in treating INRs. The TPL would be the major bioactive compound to inhibit the IFN response and the phosphorylation of STAT1. Our observations suggest the basis for further application of TPL analogous in treating INRs.

Address: Tsinghua-Peking Center for Life Sciences, Beijing, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China; Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.; Department of Infectious Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.; Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.; Tsinghua-Peking Center for Life Sciences, Beijing, China; Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, China; Department of Infectious Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. Electronic address: [email protected].

DOI: 10.1016/j.phymed.2022.154103