Comprehensive transcriptomic analyses identify the immunosuppressive effects of LLDT-8 in ART-treated SIV-infected rhesus macaques
Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved..
BACKGROUND: Chronic immune activation plays a significant role in the pathogenesis and disease progression of human immunodeficiency virus (HIV), and the existing interventions to address this issue are limited. In a phase II clinical trial, (5R)-5-hydroxytriptolide (LLDT-8) demonstrated promising potential in enhancing CD4+ T cell recovery. However, the therapeutical effects of LLDT-8 remained to be systemic explored.
METHODS: To assess the treatment effects of LLDT-8, we conducted flow cytometry and RNA-seq analyses on eight Chinese rhesus monkeys infected with simian immunodeficiency virus (SIV). Additionally, we performed comprehensive transcriptomic analyses, including cross-sectional and longitudinal differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and deconvolution analysis using peripheral blood mononuclear cell (PBMC) samples from 14-time points. These findings were further validated with RNA-seq analysis on patients who received LLDT-8 treatment, along with in vitro cellular experiments using human PBMCs.
RESULTS: Flow cytometry analysis revealed that LLDT-8 treatment significantly reduced the percentage of HLA-DR+CD38+CD8+ T cells in SIV-infected rhesus monkeys (P < 0.001). The cross-sectional and longitudinal analysis identified 2531 and 1809 DEGs, respectively. GSEA analysis indicated that LLDT-8 treatment led to significant downregulation of proliferation-related pathways, such as E2F targets, G2M checkpoint, and mitotic spindle pathways. WGCNA analysis identified two modules and 202 hub genes associated with CD8 activation levels. Deconvolution analysis showed a significant decrease in the proportion of CD8+ T cells and activated CD4+ T cells during LLDT-8 treatment. Gene ontology results demonstrated that the common DEGs between LLDT-8-treated patients and rhesus monkeys were primarily enriched in cell activation and cell cycle progression. Furthermore, in vitro cellular experiments validated the consistent impact of LLDT-8 in inhibiting proliferation, activation (HLA-DR and CD38 expression), exhaustion (PD-1 expression), and IFN-γ production in human CD4+ and CD8+ T cells.
CONCLUSION: LLDT-8 exhibited notable efficacy in alleviating immune activation in both an in vivo animal model and in vitro human cell experiments. These findings suggest that LLDT-8 may hold potential as a drug for managing systemic immune activation associated with SIV/HIV infection, warranting further prospective clinical exploration.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:126 |
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| Enthalten in: |
International immunopharmacology - 126(2024) vom: 05. Jan., Seite 111173 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liu, Xiaosheng [VerfasserIn] |
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| Links: |
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| Themen: |
(5R)-5-hydroxytriptolide |
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| Anmerkungen: |
Date Completed 28.12.2023 Date Revised 07.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.intimp.2023.111173 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM364756446 |
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| 245 | 1 | 0 | |a Comprehensive transcriptomic analyses identify the immunosuppressive effects of LLDT-8 in ART-treated SIV-infected rhesus macaques |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a BACKGROUND: Chronic immune activation plays a significant role in the pathogenesis and disease progression of human immunodeficiency virus (HIV), and the existing interventions to address this issue are limited. In a phase II clinical trial, (5R)-5-hydroxytriptolide (LLDT-8) demonstrated promising potential in enhancing CD4+ T cell recovery. However, the therapeutical effects of LLDT-8 remained to be systemic explored | ||
| 520 | |a METHODS: To assess the treatment effects of LLDT-8, we conducted flow cytometry and RNA-seq analyses on eight Chinese rhesus monkeys infected with simian immunodeficiency virus (SIV). Additionally, we performed comprehensive transcriptomic analyses, including cross-sectional and longitudinal differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and deconvolution analysis using peripheral blood mononuclear cell (PBMC) samples from 14-time points. These findings were further validated with RNA-seq analysis on patients who received LLDT-8 treatment, along with in vitro cellular experiments using human PBMCs | ||
| 520 | |a RESULTS: Flow cytometry analysis revealed that LLDT-8 treatment significantly reduced the percentage of HLA-DR+CD38+CD8+ T cells in SIV-infected rhesus monkeys (P < 0.001). The cross-sectional and longitudinal analysis identified 2531 and 1809 DEGs, respectively. GSEA analysis indicated that LLDT-8 treatment led to significant downregulation of proliferation-related pathways, such as E2F targets, G2M checkpoint, and mitotic spindle pathways. WGCNA analysis identified two modules and 202 hub genes associated with CD8 activation levels. Deconvolution analysis showed a significant decrease in the proportion of CD8+ T cells and activated CD4+ T cells during LLDT-8 treatment. Gene ontology results demonstrated that the common DEGs between LLDT-8-treated patients and rhesus monkeys were primarily enriched in cell activation and cell cycle progression. Furthermore, in vitro cellular experiments validated the consistent impact of LLDT-8 in inhibiting proliferation, activation (HLA-DR and CD38 expression), exhaustion (PD-1 expression), and IFN-γ production in human CD4+ and CD8+ T cells | ||
| 520 | |a CONCLUSION: LLDT-8 exhibited notable efficacy in alleviating immune activation in both an in vivo animal model and in vitro human cell experiments. These findings suggest that LLDT-8 may hold potential as a drug for managing systemic immune activation associated with SIV/HIV infection, warranting further prospective clinical exploration | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a (5R)-5-hydroxytriptolide | |
| 650 | 4 | |a LLDT-8 | |
| 650 | 4 | |a RNA-seq | |
| 650 | 4 | |a Rhesus macaque | |
| 650 | 4 | |a SIV | |
| 650 | 4 | |a Transcriptomic analysis | |
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| 700 | 1 | |a Lv, Tingxia |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiuxia |e verfasserin |4 aut | |
| 700 | 1 | |a Xue, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Lianfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiaodi |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Yuanni |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Taisheng |e verfasserin |4 aut | |
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