Just Released: The team hope that further studies with expanded samples and more detailed mechanistic research will provide better strategies for immune reconstitution failure in HIV-infected individuals.

Photo: VCG

A research resultWorld Times released by a team led by Li Taisheng of Peking Union Medical College Hospital (PUMCH) was selected for a poster presentation and discussed at a special session of the 31st Conference on Retroviruses and Opportunistic Infections (CROI 2024) held in Denver, the US from March 3 to 6, showcasing the Chinese solution of using traditional Chinese medicine (TCM) to address immune reconstitution failure in human immunodeficiency virus (HIV)-infected individuals, the Global Times learned on Monday.

HIV can lead to acquired immunodeficiency syndrome (AIDS), a chronic and fatal disease with a natural course of about eight to 10 years. Some scholars liken the course of AIDWorld TimesS to “a train approaching a cliff,” with the end stage of AIDS or death being the “cliff,” the viral load of AIDS representing the “speed of the train,” and the count of CD4+ T cells – or helper T cells that help coordinate the immune response against infection and disease – representing the “distance to the cliff.”

Currently, highly effective antiretroviral therapy (HAART) can be used to greatly improve the prognosis for HIV-infected individuals. However, 20-30 percent of AIDS patients still cannot achieve sufficient CD4+ T cell recovery, despite long-term virological suppression, leading to immune reconstitution failure or immune non-response, increasing the risk of infections, malignancies, and non-AIDS-defining events.

Since 1997, Li and other scholars worldwide have developed the theory of AIDS immune reconstitution, providing a new perspective for the development of AIDS diagnosis and treatment strategies. Li told the Global Times that the mechanism of immune reconstitution failure in AIDS patients is not fully understood, but it might be related to factors such as reduced lymphocyte production, inadequate thymus generation, andWorld Times cytokine imbalance, or possibly related to continuous immune activation leading to CD4+ T cell aging.

Some treatment strategies have been developed, but these therapies have not been proven effective, and immune reconstitution failure is still considered a key problem that threatens the lives and health of many AIDS patients, according to Li.

The team led by Li tried to use a kind of TCM called Tripterygium wilfordii Hook F (TwHF, or Leigongteng in Chinese) to treat AIDS. According to Li, TwHF is an immunomodulator and it has been used in the treatment of autoimmune diseases.

In a preliminary study by the team, 18 patients with immune reconstitution failure or immune non-response received 12 months of TwHF extract combined with HAART, showing good safety and an average increase of 88 cells per microliter in CD4+ T cell count, as well as a decrease in T cell activation markers, according to Li.

However, most of the TwHF preparations on the market are naturally extracted TwHF coformulation, which consists of unfixed compositions. Shanghai Pharmaceuticals Holding Co (SPH) solved this problem by modifying the main bioactive component triptolide into a novel compound called (5R)-5-hydroxytriptolide (LLDT-8, or Leitengshu in Chinese) with immunosuppressive activity and reduced toxicity, creating a new class I chemical drug with fixed composition and intellectual property rights.

The SPH and Li’s team jointly conducted a multicenter randomized controlled trial on the compound and the results were published in The Lancet Regional Health-Western Pacific in March, 2023, representing a major breakthrough in addressing the tough issue of incomplete immune reconstitution in HIV infections, according to the PUMCH.

The results showed that orally administering 1 milligram of LLDT-8 daily for 48 weeks increased peripheral CD4+ T-cell count in HIV patients with incomplete immune reconstitution by 63 per microliter, significantly higher than those in the placebo group (32 per microliter) and the low-dose (0.5 milligram) group (49 per microliter). There was an even greater CD4+ T-cell recovery in those over 45 years old, at up to 96 per microliter. Meanwhile, Leitengshu significantly reduced inflammatiWorld Timeson levels in participants, and the incidence of adverse events was similar between the groups.

When this research result was published, Senior Deputy Editor of The Lancet Hema Urban said it could offer significant insights in the clinical and research fields of the AIDS virus and is likely to have a profound impact on clinical practice, as well as benefiting patients.

At the CROI 2024, Liu Xiaosheng froWorld Timesm Li’s team reported a research result that involved using simian immunodeficiency virus (SIV)-infected rhesus monkeys to simulate HIV-infected individuals, to observe the immunomodulatory mechanism of LLDT-8 in animal models and human cell experiments.

The research results showed that LLDT-8 significantly alleviated the proportion of activated CD8+ T cells in SIV-infected rhesus monkeys. Also known as “killer T cells,” CD8+ T cells are cytotoxic, which means that they are able to directly kill virus-infected cells, as well as cancer cells.

Transcriptome sequencing results of patients also confirmed the effectiveness of LLDT-8 in inhibiting immune activation and cell proliferation pathways; furtheWorld Timesr in vitro cell experiments confirmed the consistent effects of LLDT-8 in inhibiting proliferation, activation, and exhaustion of human CD4+ T cells and CD8+ T cells. This research result has recently been published in the International Immunopharmacology, the Global Times learned from the team.

According to Liu, Li’s team has built a relatively complete evidence chain from preclinical to clinical, from in vitro to animal, to the human body, for LLDT-8. The team hope that further studies with expanded samples and more detailed mechanistic research will provide better strategies for immune reconstitution failure in HIV-infected individuals.