Paclitaxel-induced immune dysfunction and activation of transcription factor AP-1 facilitate Hepatitis B virus replication

Background and Aims

Hepatitis B virus (HBV) reactivation is commonly observed in individuals with chronic HBV infection undergoing antineoplastic drug therapy. Paclitaxel (PTX) treatment has been identified as a potential trigger for HBV reactivation. This study aimed to uncover the mechanisms of PTX-induced HBV reactivation in vitro and in vivo, which may inform new strategies for HBV antiviral treatment.

Methods

The impact of PTX on HBV replication was assessed through various methods including enzyme-linked immunosorbent assay, dual-luciferase reporter assay, quantitative real-time PCR, chromatin immunoprecipitation, and immunohistochemical staining. Transcriptome sequencing and 16S rRNA sequencing were employed to assess alterations in the transcriptome and microbial diversity in PTX-treated HBV transgenic mice.

Results

PTX enhanced the levels of HBV 3.5-kb mRNA, HBV DNA, HBeAg, and HBsAg both in vitro and in vivo. PTX also promoted the activity of the HBV core promoter and transcription factor AP-1. Inhibition of AP-1 gene expression markedly suppressed PTX-induced HBV reactivation. Transcriptome sequencing revealed that PTX activated the immune-related signaling networks such as IL-17, NF-κB, and MAPK signaling pathways, with the pivotal common key molecule being AP-1. The 16S rRNA sequencing revealed that PTX induced dysbiosis of gut microbiota.

Conclusions

In this study, PTX treatment was found to directly promote HBV replication and transcription, leading to HBV reactivation in HBV stable expression cell models, HBV natural infection cell models, and HBV transgenic mouse models. Further molecular analysis indicated that PTX may enhance HBV replication and transcription through the promotion of HBV core promoter activity mediated by the transcription factor AP-1. Furthermore, PTX treatment was found to induce immune system dysregulation and dysbiosis of the gut microbiota, which may potentially contribute to the induction of HBV reactivation. However, it is important to acknowledge that our experimental models may not fully replicate the complex dynamics of HBV infection and reactivation observed in clinical patients. Therefore, more comprehensive and in-depth research is required to provide references for the development of prevention and treatment strategies for clinical HBV reactivation.

Full text

https://www.xiahepublishing.com/2310-8819/JCTH-2023-00537

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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