Recently, at the 31st Conference on Retroviruses and Opportunistic Infections (CROI 2024) held in the United States, a research achievement from Professor Li Taisheng's team at Peking Union Medical College Hospital was featured in a poster presentation. The study found that Hydroxyl Lidanxiong Alcohol (LLDT-8), a newly developed National Class I drug derived from Tripterygium wilfordii Hook F, effectively enhances the CD4+ T lymphocyte count in AIDS patients with long-term antiviral therapy-induced immune reconstitution failure. This research showcases the "Concord Protocol" for addressing immune reconstitution failure in HIV-infected individuals to scholars worldwide.
In previous studies, Professor Li Taisheng and his team discovered that impaired function of the human thymus tissue due to viral infection is one of the reasons for immune reconstitution failure in AIDS patients. Additionally, chronic abnormal inflammation in patients also contributes to immune reconstitution failure in some cases. To address this issue, various drug trials have been conducted internationally, including interleukin-2, chloroquine, etc., all of which have clinically ended in failure.
Tripterygium wilfordii Hook F, commonly known as Thunder God Vine, possesses immunomodulatory and anti-inflammatory properties and has long been used in the treatment of rheumatic immune diseases such as arthritis. In a preliminary study previously published by Professor Li Taisheng's team, 18 immune reconstitution failure or immunological non-response patients (INRs) received 12 months of Tripterygium wilfordii extract combined with antiretroviral therapy (ART), demonstrating good safety and an average increase of 88 cells/μl in CD4+ T cell count, along with reduced T cell activation markers. Transcriptomic and proteomic studies have also shown that upregulation of the interferon (IFN) signaling pathway is a significant feature of INRs, while the main bioactive component, Hydroxyl Lidanxiong Alcohol (LLDT-8), in Thunder God Vine can reduce the activity of the IFN signaling pathway.
LLDT-8 is a modified active extract of Tripterygium wilfordii Hook F (5R)-5-Hydroxyl Lidanxiong Alcohol (LLDT-8), characterized by immunosuppressive activity and reduced toxicity. A nationwide multicenter randomized controlled Phase II study (NCT04084444) led by Professor Li Taisheng, published in The Lancet Regional Health – Western Pacific, showed that among immune reconstitution failure patients receiving high-dose LLDT-8, low-dose LLDT-8, or placebo treatment, CD4+ T cell counts increased by 63 cells/μl, 49 cells/μl, and 32 cells/μl respectively, with significant improvement observed in the high-dose group compared to the placebo group.
At the CROI conference, Dr. Liu Xiaosheng from Professor Li Taisheng's team further reported a research outcome using rhesus macaques infected with simian immunodeficiency virus (SIV) to mimic HIV-infected individuals, aiming to observe the immunomodulatory mechanisms of LLDT-8 in both in vivo animal models and in vitro human cell experiments.
The results showed that LLDT-8 significantly alleviated the proportion of activated CD8+ T cells (HLA-DR and CD38 expression) in SIV-infected rhesus macaques; through transcriptomic time-series analysis and gene set enrichment analysis (GSEA), LLDT-8 downregulated proliferation-related pathways in rhesus macaques, including E2F targets, G2M checkpoints, and mitotic spindle pathways; transcriptomic sequencing results from patients also confirmed the effectiveness of LLDT-8 in inhibiting immune activation and cell proliferation pathways; further in vitro cell experiments confirmed consistent effects of LLDT-8 in inhibiting proliferation, activation (HLA-DR and CD38 expression), exhaustion (PD-1 expression), and IFN-γ production of human CD4+ T cells and CD8+ T cells. This research outcome has recently been published in the International Immunopharmacology journal.
It is understood that Professor Li Taisheng's team has long been committed to unraveling strategies for immune reconstitution failure. In addition to the aforementioned in vitro and animal studies, preliminary multicenter randomized controlled Phase II studies have also confirmed the efficacy and safety of LLDT-8 in improving CD4+ T cell counts. Currently, the team has built a relatively complete evidence chain of evidence for LLDT-8, a Class I chemical new drug with independent intellectual property rights, from preclinical to clinical stages, from in vitro to animal models and then to humans. Professor Li Taisheng expressed anticipation for further studies with expanded samples and more detailed mechanistic research to provide better strategies for improving immune reconstitution failure in HIV-infected individuals in the future.
