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-B,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:PTX-induced HBV reactivation was likely a synergistic outcome of immune suppression and direct stimulation of HBV replication through the enhancement of HBV core promoter activity mediated by the transcription factor AP-1.These findings propose a novel molecular mechanism,underscoring the critical role of AP-1 in PTX-induced HBV reactivation.

Real-world effectiveness of an intranasal spray A8G6 antibody cocktail in the post-exposure prophylaxis of COVID-19

Previously,we identified an antibody combination A8G6 that showed promising efficacy in COVID-19 animal models and favorable safety profile in preclinical models as well as in a first-in-human trial.To evaluate the real-word efficacy of A8G6 neutralizing antibody nasal spray in post-exposure prophylaxis of COVID-19,an open-label,non-randomized,two-arm,blank-controlled,investigator-initiated trial was conducted in Chongqing,China(the register number:ChiCTR2200066416).High-risk healthy participants(18–65 years)within 72 h after close contact to COVID-19 patients were recruited and received a three-dose(1.4 mg/dose)A8G6 treatment daily or no treatment(blank control)for 7 consecutive days.SARS-CoV-2 infection occurred in 151/340(44.4%)subjects in the blank control group and 12/173(6.9%)subjects in the A8G6 treatment group.The prevention efficacy of the A8G6 treatment within 72 h exposure was calculated to be 84.4%(95%CI:74.4–90.4%).Moreover,compared to the blank-control group,the time from the SARS-CoV-2 negative to the positive COVID-19 conversion was significantly longer in the AG86 treatment group(mean time:3.4 days vs 2.6 days,p=0.019).In the secondary end-point analysis,the A8G6 nasal treatment had no effects on the viral load at baseline SARS-CoV-2 RT-PCR positivity and the time of the negative COVID-19 conversion.Finally,except for 5 participants(3.1%)with general adverse effects,we did not observe any severe adverse effects related to the A8G6 treatment.In this study,the intranasal spray AG86 antibody cocktail showed potent efficacy for prevention of SARS-CoV-2 infection in close contacts of COVID-19 patients.