At the 31st Conference on Retroviruses and Opportunistic Infections (CROI 2024) held from March 3 to 6 in Denver, Colorado, USA, a study by Dr. Taisheng Li’s team from the Peking Union Medical College Hospital was selected for a poster presentation and discussed at the fifth session. This conference, which started in 1993, has become one of the most influential meetings in the field of AIDS, attracting experts from around the world to share their latest research findings. The study presented by Dr. Li’s team showcased a “Chinese solution” for addressing immune reconstitution deficiencies in HIV-infected individuals to the global academic community.
Immune reconstitution deficiency is a significant challenge for people living with HIV (PLWH), described metaphorically as a train rushing towards a cliff, with AIDS or death representing the cliff. The speed of the train is represented by the viral load, and the distance to the cliff by the CD4 cell count. Despite the substantial improvements in prognosis for PLWH due to highly active antiretroviral therapy (HAART), also known as “cocktail therapy,” 20% to 30% of patients achieve long-term virological suppression but fail to sufficiently recover CD4+ T cells. This condition is known as immune reconstitution deficiency or immunological non-response (INRs), increasing the risk of opportunistic infections, malignancies, and non-AIDS related complications. Since 1997, Dr. Taisheng Li, along with other scholars worldwide, has developed the theory of AIDS immune reconstitution, providing a new perspective for the development of diagnostic and therapeutic approaches for AIDS.
The mechanisms behind immune reconstitution deficiencies in HIV-infected patients are not fully understood but are thought to be related to reduced lymphocyte production (such as in aging, insufficient thymic output, and cytokine dysregulation) and persistent immune activation leading to CD4+ T cell aging and apoptosis. Various therapeutic strategies have been developed, including the use of recombinant human interleukins (IL-2, IL-7), cell growth factors, and immunomodulators such as chloroquine, hydroxychloroquine, and metformin. However, these therapies have not proven effective in prospective studies, leaving immune reconstitution deficiency as a significant threat to the health and lives of many HIV-infected individuals.
In the treasure trove of traditional Chinese medicine, a promising solution for improving immune reconstitution deficiency has been found. Tripterygium wilfordii, a Chinese herbal immunomodulator used for treating autoimmune diseases, has shown promise. Dr. Taisheng Li’s team previously published a preliminary study where 18 INRs received 12 months of Tripterygium wilfordii extract combined with ART treatment, demonstrating good safety and an average increase of 88 cells/μl in CD4+ T cell counts, along with a reduction in T cell activation markers. Transcriptomic and proteomic studies also revealed that upregulation of the interferon (IFN) signaling pathway is a significant characteristic of INRs, and the main bioactive component of Tripterygium wilfordii, triptolide, can reduce the activity of the IFN signaling pathway.
Leitengshu, a modified active extract of Tripterygium wilfordii (5R)-5-hydroxytriptolide (LLDT-8), has been shown to possess immunosuppressive activity with reduced toxicity. A nationwide multicenter randomized controlled phase II study (NCT04084444) led by Dr. Li, published in The Lancet Regional Health–Western Pacific, showed that patients with immune reconstitution deficiency treated with high-dose LLDT-8, low-dose LLDT-8, or placebo experienced CD4+ T cell count increases of 63 cells/μl, 49 cells/μl, and 32 cells/μl, respectively, with the high-dose group showing significant improvement over the placebo group (P=0.036). The study’s results, highly praised by Hema Urban, senior editor at The Lancet journals, are considered to bring significant insights to the clinical and research fields of HIV, potentially having a profound impact on clinical practice in the field.
At CROI 2024, Dr. Liu Xiaosheng from Dr. Li’s team reported further research using simian immunodeficiency virus (SIV)-infected rhesus monkeys to model HIV infection and observe the immunomodulatory mechanism of LLDT-8 in vivo and in vitro. The results showed that LLDT-8 significantly alleviated CD8+ T cell activation in SIV-infected rhesus monkeys and downregulated proliferation-related pathways, including E2F targets, G2M checkpoint, and mitotic spindle pathways, in transcriptome time series and gene set enrichment analysis (GSEA). The transcriptome sequencing results of patients also confirmed the effectiveness of LLDT-8 in suppressing immune activation and cell proliferation pathways
Building a Complete Evidence Chain: China’s Immune Reconstitution Deficiency Solution Gains International Attention
The latest research from Dr. Taisheng Li’s team was also selected for the fifth thematic discussion session (Themed Discussion-05) at the 2024 CROI Conference. Founded in 1993, the CROI Conference aims to promote academic exchange in epidemiological and biological research on retroviruses and related diseases. The conference covers a wide range of topics, including Human Immunodeficiency Virus (HIV), hepatitis viruses, the novel coronavirus, monkeypox virus, and other viral infections. Over 31 years, the CROI Conference has become a significant specialty meeting in the field of infectious diseases, especially in AIDS diagnosis and treatment. Every year, the CROI Conference reports on new topics, concepts, and medications, from updates on each generation of ART to reports on curative therapies and cases of AIDS.
Persistent immune activation and inflammation in HIV-infected individuals is one of the critical theories explaining immune reconstitution deficiency, and new treatments targeting this theory have become a hot research topic. Thus, this year’s conference specially set up a session themed “Persistent Immune Activation and Inflammation During Antiretroviral Therapy,” selecting five research findings for discussion. This session covered the detection of long-term abnormal immune activation, pathogenesis, and treatment strategies, representing the forefront of exploration in this area. The session, chaired by Dr. Frank Maldarelli from the National Cancer Institute (NCI) and other attending experts, showed keen interest in the progress of the research on LLDT-8 treatment for HIV immune reconstitution deficiency reported by Dr. Liu Xiaosheng.
Dr. Xiaosheng Liu explained that Dr. Taisheng Li’s team has been committed to developing strategies to tackle immune reconstitution deficiency. Beyond the aforementioned in vitro and animal studies, a preliminary multicenter randomized controlled phase II trial has also confirmed the efficacy and safety of LLDT-8 in improving CD4+ T cell counts. With support from the “13th Five-Year” Major Project on Infectious Diseases by the Ministry of Science and Technology, and clinical research projects of central high-level hospitals, Dr. Li’s team has now established a relatively complete evidence chain for LLDT-8, a Class I new chemical drug with independent intellectual property rights, covering preclinical to clinical stages, and from in vitro to animal and human studies. Looking forward, there is hope for further expanded sample size studies and more detailed mechanism investigations to provide better strategies for improving immune reconstitution deficiency in people living with HIV.
Dr. Taisheng Li, MD, PhD
Director of Infectious Diseases Department, Peking Union Medical College Hospital
