JHEP Reports最新文献

{"title":"Reply to: “Dynamic imaging of macrophages in MASLD: A major interest in insulin resistance and outside the liver”","authors":"Yongjian Liu , Joel D. Schilling","doi":"10.1016/j.jhepr.2025.101386","DOIUrl":"10.1016/j.jhepr.2025.101386","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101386"},"PeriodicalIF":9.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of Rocahepevirus ratti (rat hepatitis E virus) in humans and rats in China","authors":"Xiuji Cui ,&nbsp;Jianwen Situ ,&nbsp;Ting Tang ,&nbsp;Zhiyu Li ,&nbsp;Dongzhui Chen ,&nbsp;Stanley Siu-Fung Ho ,&nbsp;Hiu-Laam Chung ,&nbsp;Tsz-Chung Wong ,&nbsp;Yonghao Liang ,&nbsp;Chaowen Deng ,&nbsp;Yongxian Su ,&nbsp;Huijun Cai ,&nbsp;Simon Kam-Fai Lo ,&nbsp;Shiyao Huang ,&nbsp;Sheng Zeng ,&nbsp;Liyuan Zhang ,&nbsp;Yunchun Chen ,&nbsp;Shusheng Wu ,&nbsp;Estie Hon-Kiu Shun ,&nbsp;Nicholas Foo-Siong Chew ,&nbsp;Siddharth Sridhar","doi":"10.1016/j.jhepr.2025.101370","DOIUrl":"10.1016/j.jhepr.2025.101370","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div><em>Rocahepevirus ratti</em> (rat hepatitis E virus; rHEV) is a ubiquitous pathogen of rats that has recently emerged as a cause of hepatitis in humans. Although several rHEV cases have been detected worldwide, the extent of human exposure to this hepatitis agent is still poorly defined. We conducted a multicenter surveillance study in China examining rHEV exposures in demographically diverse human populations from a One Health perspective.</div></div><div><h3>Methods</h3><div>In this multicenter cross-sectional study, we used fully validated rHEV IgG enzymatic immunoassays and reverse transcription PCR in 1,199 individuals with (n = 655) or without hepatitis (n = 544) recruited from three centers in China (Hainan, Hong Kong, and Shenzhen). The patient population included both urban and rural populations. Characteristics of infected individuals and phylogenetic links with rat epizootics were described.</div></div><div><h3>Results</h3><div>rHEV IgG seroprevalence was higher in the rural Hainan cohort (15/229, 6.6%) compared with Shenzhen (9/427, 2.1%) and Hong Kong cohorts (2/543, 0.4%) (<em>p</em> &lt;0.0001). This difference persisted on multivariable logistic regression with an adjusted odds ratio of 20.52 (95% CI: 13.86–30.39). rHEV exposure was also associated with increasing age and environmental rodent exposure. We observed rHEV viraemia in two hepatitis patients (2/655; 0.3%) in Hainan and Hong Kong with hepatitis B and renal transplantation, respectively. The latter developed chronic hepatitis E. 19/509 (3.7%) rats captured in Hainan harbored rHEV. Both human rHEV isolates were phylogenetically related to rodent-derived rHEV strains circulating in Hainan and Hong Kong, respectively.</div></div><div><h3>Conclusions</h3><div>Humans are intermittently exposed to rHEV, especially in rural settings with rodent exposure. Overt hepatitis occurs in individuals with liver disease or immunosuppression. Spillover strains are related to epizootics in rodents offering opportunities for targeted disinfestation.</div></div><div><h3>Impact and implications</h3><div>Building on our previous work finding that <em>Rocahepevirus ratti</em> (rHEV) is a novel cause of sporadic viral hepatitis in humans, we studied rHEV exposures in humans from various epidemiological settings. We found intermittent exposure to rat hepatitis E in individuals living in both urban and rural settings with a markedly higher seroprevalence in the latter. Spillover viremic infections in individuals with underlying liver disease or immunosuppression were closely linked to epizootic rHEV strains circulating in rodents. Physicians and diagnostic laboratories should incorporate rHEV testing in algorithms for viral hepatitis while policymakers should consider rHEV surveillance in rodents to guide disinfestation efforts.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101370"},"PeriodicalIF":9.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage-derived IL-15 imprints peritoneal TRM-like CD8 T cells in cirrhosis and spontaneous bacterial peritonitis","authors":"Oluwatomi Ibidapo-Obe ,&nbsp;Sven Stengel ,&nbsp;Mick Frissen ,&nbsp;Johanna Reißing ,&nbsp;Karsten Große ,&nbsp;Michael Rooney ,&nbsp;Stefanie Quickert ,&nbsp;Trong-Hieu Nguyen ,&nbsp;Sabine Baumgart ,&nbsp;Hector Leal-Lassalle ,&nbsp;Raquel Benedé-Ubieto ,&nbsp;Yulia A. Nevzorova ,&nbsp;Tony Bruns","doi":"10.1016/j.jhepr.2025.101381","DOIUrl":"10.1016/j.jhepr.2025.101381","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Tissue-resident memory T cells (TRMs) are long-lived cells poised for rapid immune responses to pathogens. This study assesses whether peritoneal CD8 T cells from patients with cirrhosis exhibit TRM-like functionalities, focusing on how inflammatory events shape phenotype and function.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Peritoneal CD8 T cell subsets from patients with decompensated cirrhosis were analysed using mass cytometry, flow cytometry, RT-qPCR, single-cell RNA sequencing, &lt;em&gt;in vitro&lt;/em&gt; culture, and cytokine profiling. Cells from 87 patients were used, of which 30 experienced spontaneous bacterial peritonitis (SBP). Soluble co-inhibitory (checkpoint) receptors were investigated in cell-free ascites from 80 patients, and TRM-activating cytokines were quantified in peritoneal macrophages.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Unsupervised mass cytometry and subsequent flow cytometry validation confirmed the peritoneal abundance of CD103+ CD69+ CD8+ memory T cells in ascites compared with blood (2.2% &lt;em&gt;vs.&lt;/em&gt; 0.4%; &lt;em&gt;p&lt;/em&gt; &lt;0.001). TRM-like cells, particularly the CD49a+ subset, were robust producers of interferon-γ (IFN-γ) post-T cell receptor ligation (35.1% &lt;em&gt;vs.&lt;/em&gt; 15.3% in CD49- TRM-like cells; &lt;em&gt;p&lt;/em&gt; &lt;0.001), and were susceptible to bystander activation by IL-15. Single-cell RNA sequencing revealed tissue residency markers alongside transcriptional signatures of activation and exhaustion in IL-15-exposed peritoneal CD8 T cells. Peritoneal macrophages emerged as IL-15 sources during SBP (ascitic fluid concentration 18.6 pg/ml &lt;em&gt;vs.&lt;/em&gt; 8.9 pg/ml; &lt;em&gt;p&lt;/em&gt; &lt;0.05), altering TRM-like cell phenotype even after inflammation had subsided. Despite the expression of co-inhibitory receptors, TRM-like cells maintained cytotoxic effector functions in a soluble checkpoint-rich environment, with PD-1/PDL-1 axis blockade not affecting their cytotoxic capacity.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;A subset of peritoneal CD8 T cells exhibits TRM-like traits and responds to macrophage-derived cytokines during peritoneal inflammation. TRM-like cells retain potent cytotoxic and proinflammatory responses after SBP resolution, underscoring their role in modulating peritoneal immunity and inflammation in cirrhosis.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Patients with decompensated cirrhosis exhibit impaired immune responses increasing the risk of spontaneous bacterial peritonitis. This study provides insight into a subset of human peritoneal CD8 T cells in patients with decompensated cirrhosis that have a long-lived and tissue-resident phenotype capable of effectively fighting recognised pathogens within a short period with the help of IL-15 produced by activated macrophages in a bystander fashion. This knowledge has the potential to improve immunomodulatory therapies aiming to enhance peritoneal immune surveillance, and by targeting TRM-like cells and/or IL-15 signalli","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 6","pages":"Article 101381"},"PeriodicalIF":9.5,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum regarding previously published articles","authors":"","doi":"10.1016/j.jhepr.2025.101359","DOIUrl":"10.1016/j.jhepr.2025.101359","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101359"},"PeriodicalIF":9.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Copyright and information","authors":"","doi":"10.1016/S2589-5559(25)00055-2","DOIUrl":"10.1016/S2589-5559(25)00055-2","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101378"},"PeriodicalIF":9.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatic immune environment differences among common mouse strains in models of MASH and liver cancer","authors":"Patrick Huang ,&nbsp;Francisco J. Rodriguez-Matos ,&nbsp;Jonathan Qi ,&nbsp;Rajiv Trehan ,&nbsp;Yuta Myojin ,&nbsp;Xiao Bin Zhu ,&nbsp;Tim F. Greten ,&nbsp;Chi Ma","doi":"10.1016/j.jhepr.2025.101380","DOIUrl":"10.1016/j.jhepr.2025.101380","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Inbred mouse strains are critical tools for studying immune regulation of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Here, we profiled mouse strain-associated hepatic immune differences, and performed mice–human cross-species immune comparisons.</div></div><div><h3>Methods</h3><div>Immune landscapes of C57BL/6, BALB/c, and FVB/N mice were compared under healthy, MASH, or HCC state using high-dimensional spectral flow cytometry (n = 4 per condition). MASH was induced by feeding methionine- and choline-deficient or Western diet + carbon tetrachloride. HCC was caused by hydrodynamic plasmid injection of MYC/sg-p53. Public mouse and human scRNA-seq datasets were used for validation and cross-species comparisons.</div></div><div><h3>Results</h3><div>In healthy mice, liver CD4⁺ T (24% <em>vs.</em> 14% <em>vs.</em> 34%, <em>p</em> &lt;0.05) and B cells (36.5% <em>vs.</em> 35% <em>vs.</em>18%, <em>p</em> &lt;0.05) varied the most among three strains. C57BL/6 mice showed T_H1 dominance, whereas BALB/c and FVB/N mice had T_H2 dominance (log[T_H1:T_H2] = 0.17, -0.31, -0.17). In MASH mice, expansion of liver myeloid cells and innate lymphocytes were commonly found, but changes of B cells (log(fold-change) = -0.38, -0.28, -0.58, <em>p</em> &lt;0.05) and T subsets (<em>e.g.</em> CD4⁺ T log(fold-change) = -0.21, -0.07, -0.15, <em>p</em> &lt;0.05) varied greatly among strains. MYC/sg-p53 HCC induced a consistent expansion of liver Tregs and CD8⁺ T cells (<em>p</em> &lt;0.05), but differential shifts of liver immune landscape were seen among strains. The flow cytometry data was supported by public scRNA-seq datasets matching C57BL/6 background. Further cross-species comparison in MASH condition confirmed shared changes of adaptive lymphocytes between mice and humans. In two MASH models, BALB/c or C57BL/6 mice were more consistent to recapture loss of CD4⁺ T or B cells, respectively (<em>p</em> &lt;0.05).</div></div><div><h3>Conclusions</h3><div>Substantial liver immune differences exist among common mouse strains. Mice can recapitulate certain human liver immune changes with strain variations.</div></div><div><h3>Impact and implications</h3><div>Our immune cell profiling study revealed that the liver immune environment can be quite different among common mouse strains both under healthy and pathologic states, such as steatohepatitis or neoplastic processes. Our results serve as a data resource for studies investigating liver immunology and provide valuable insights for the design of studies on various immune cells in the livers of mice.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101380"},"PeriodicalIF":9.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Board page","authors":"","doi":"10.1016/S2589-5559(25)00052-7","DOIUrl":"10.1016/S2589-5559(25)00052-7","url":null,"abstract":"","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101375"},"PeriodicalIF":9.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipidomics-based plasma signature of alcohol-related hepatitis linked to short-term mortality","authors":"Florent Artru ,&nbsp;Stephen Atkinson ,&nbsp;Francesca Trovato ,&nbsp;Luke D. Tyson ,&nbsp;Vishal C. Patel ,&nbsp;Nikhil Vergis ,&nbsp;Noora Kano ,&nbsp;Robert Goldin ,&nbsp;Alberto Quaglia ,&nbsp;Alexandros Pechlivanis ,&nbsp;Phillip Morgan ,&nbsp;Salma Mujib ,&nbsp;Anna Cavazza ,&nbsp;Ellen Jerome ,&nbsp;Marc Zentar ,&nbsp;Roosey Sheth ,&nbsp;Maura Morrison ,&nbsp;Evangelos Triantafyllou ,&nbsp;Elaine Holmes ,&nbsp;María Gómez-Romero ,&nbsp;Mark Thursz","doi":"10.1016/j.jhepr.2025.101367","DOIUrl":"10.1016/j.jhepr.2025.101367","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Severe alcohol-related hepatitis (sAH) is an inflammatory condition with high short-term mortality. Hypothesis-driven approaches have failed to identify effective treatments. Given the role of lipids as inflammatory mediators, this study aimed to identify lipidomic changes and lipid species associated with sAH and mortality risk.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Untargeted lipidomics was performed on serum samples from two cohorts of patients with sAH and decompensated cirrhosis (DC). Principal component analysis and orthogonal partial least squares discriminant analysis were used to assess lipidome changes. Correlations were made with lipoproteins, lipid mediators, cytokines, cytokeratin fragments, and histological indices.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;In the first part, 78 patients with sAH were matched on bilirubin levels with 23 patients with DC. Lipidomics identified a distinct sAH signature involving glycerophospholipids, including PC(34:2) (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.45–7.05, &lt;em&gt;p&lt;/em&gt; = 0.01), PC(O–38:5) (OR 3.31, 95% CI 2.23–7.14, &lt;em&gt;p&lt;/em&gt; = 0.002), PI(38:4) (OR 0.71, 95% CI 0.46–0.88, &lt;em&gt;p&lt;/em&gt; = 0.02), and LPC(18:1) (OR 0.47, 95% CI 0.32–0.82, &lt;em&gt;p&lt;/em&gt; = 0.01). These lipids demonstrated excellent discriminatory power between sAH and DC with areas under the receiver operating characteristic curve (AUROCs) between 0.87 and 0.88. In the second part, in 159 sAH patients, specific lipids, including carnitines CAR(2:0) (OR 2.51, 95% CI 1.25–4.96, &lt;em&gt;p&lt;/em&gt; = 0.008) and CAR(16:1) (OR 2.21, 95% CI 1.09–7.48, &lt;em&gt;p&lt;/em&gt; = 0.009), were linked to 90-day mortality. Acylcarnitines correlated with disease severity parameters such as model for end-stage liver disease, pro-inflammatory cytokines levels, and hepatocyte ballooning on pathology.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;Untargeted lipidomics identified a glycerophospholipid and sphingolipid signature distinguishing sAH from DC, implicating lipid species involved in liver regeneration and immune function. Acylcarnitine accumulation in patients with sAH and poor prognosis suggests mitochondrial dysfunction and warrants further investigation into therapeutic potential.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications&lt;/h3&gt;&lt;div&gt;Lipids can act as mediators at the interface between the immune system and metabolism, potentially contributing to the pathogenesis and outcomes of patients with severe alcohol-related hepatitis, prompting us to investigate lipidomic changes in this population using untargeted approaches, compared with patients with decompensated cirrhosis. This study highlights a distinct lipidomic signature in patients with severe alcohol-related hepatitis compared with decompensated cirrhosis, primarily involving glycerophospholipids and sphingolipids. Specific lipid classes, such as acylcarnitines, suggest significant mitochondrial dysfunction and are associated with disease severity and short-term morta","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 6","pages":"Article 101367"},"PeriodicalIF":9.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel in vitro system for simultaneous infections with hepatitis B, C, D and E viruses","authors":"Roxanne Fouillé ,&nbsp;Eloi R. Verrier ,&nbsp;Amse De Meyer ,&nbsp;Lieven Verhoye ,&nbsp;Maud Michelet ,&nbsp;Romain Barnault ,&nbsp;Caroline Pons ,&nbsp;Olivier Diaz ,&nbsp;Michel Rivoire ,&nbsp;Guillaume Passot ,&nbsp;Eike Steinmann ,&nbsp;Heiner Wedemeyer ,&nbsp;Anna Salvetti ,&nbsp;Nicole Pavio ,&nbsp;Virginie Doceul ,&nbsp;Raphaël Darteil ,&nbsp;Philip Meuleman ,&nbsp;David Durantel ,&nbsp;Julie Lucifora","doi":"10.1016/j.jhepr.2025.101383","DOIUrl":"10.1016/j.jhepr.2025.101383","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>The liver, and more precisely hepatocytes, can be infected by several hepatotropic viruses, including HBV, HDV, HCV and HEV, with chronic infection leading to end-stage liver diseases. Since no <em>in vitro</em> model allowing multi-infections with the four viruses is reported, limited data are available on their interplay as well as on the potential cross-reactivity of antivirals in multi-infection cases. The aim of our study was to set up such a model.</div></div><div><h3>Methods</h3><div>HuH7.5-NTCP cells were cultured with 2% DMSO (dimethyl sulfoxide) for 1 week to allow partial differentiation into hepatocytes (dHuH7.5-NTCP) before infection with the different viruses and treatment with known antiviral molecules.</div></div><div><h3>Results</h3><div>We observed increased expression of liver specific transcripts and production of ApoB containing VLDL in dHuH7.5-NTCP cells and replication of HBV, HDV, HCV and HEV for at least 4 weeks after mono or multiple infections. We recapitulated the known antiviral effect of sofosbuvir on HCV and HEV (&gt;90% reduction in the levels of intracellular viral RNAs, <em>p</em> &lt;0.0005) and of IFN-α on HCV, HEV and HDV (80% reduction in the levels of intracellular viral RNAs, <em>p</em> &lt;0.0005). Besides its already described antiviral effect on HBV and HDV, we observed that GW4064, a farnesoid X receptor (FXR) agonist, also strongly inhibited HEV replication (85 to 95% reduction in the levels of intracellular HEV RNAs, <em>p</em> &lt;0.0005). Using HEV-infected HuHep mice, we confirmed the antiviral effect of vonafexor, an FXR agonist, that is currently being tested clinically against HBV/HDV.</div></div><div><h3>Conclusions</h3><div>We set-up the first <em>in vitro</em> model allowing multi-infections with hepatitis viruses that can be used for broad drug screening and highlighted FXR ligands as potential broad-acting antivirals.</div></div><div><h3>Impact and implications</h3><div>Hepatitis virus infections caused by HBV, HCV, HDV, and HEV represent a global health threat. Treatment options remain limited, notably due to the lack of knowledge about molecular virus-host interactions. Moreover, the interplay between these four viruses in the context of co-infections remains unknown. In this study, we report the first <em>in vitro</em> system that allows for mono and multi-infections with these four viruses and characterize the broad antiviral activity of farnesoid X receptor agonists, paving the way for the development of new strategies for viral cure.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101383"},"PeriodicalIF":9.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Auto-antibodies against interferons are common in people living with chronic hepatitis B virus infection and associate with PegIFNα non-response","authors":"Douglas L. Fink ,&nbsp;David Etoori ,&nbsp;Robert Hill ,&nbsp;Orest Idilli ,&nbsp;Nikita Kartikapallil ,&nbsp;Olivia Payne ,&nbsp;Sarah Griffith ,&nbsp;Hannah F. Bradford ,&nbsp;Claudia Mauri ,&nbsp;Patrick T.F. Kennedy ,&nbsp;Laura E. McCoy ,&nbsp;Mala K. Maini ,&nbsp;Upkar S. Gill","doi":"10.1016/j.jhepr.2025.101382","DOIUrl":"10.1016/j.jhepr.2025.101382","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Type one (T1) and three interferons (T3IFNs) are implicated in chronic hepatitis B (CHB) immunopathogenesis. IFN remains the only licenced immune modulating therapy for CHB. We measured the prevalence of auto-antibodies (auto-Abs) against T1 and T3IFNs to examine the hypothesis that they impact HBV control and treatment response, as highlighted by COVID-19.</div></div><div><h3>Methods</h3><div>Our multi-centre retrospective longitudinal study accessed two CHB cohorts; auto-Ab levels and neutralisation status were measured against T1IFN and T3IFN. Associations were tested against HBV clinical parameters.</div></div><div><h3>Results</h3><div>Overall, 16.7% (46/276) of patients with CHB had any detectable anti-IFN auto-Abs at any time and 6.5% (18/276) anti-T3IFN auto-Abs, with a high incidence of PegIFNα-induced <em>de novo</em> auto-Abs (31.4%, 11/35). However, only a minority of auto-Ab-positive sera demonstrated neutralisation <em>in vitro</em> (4/46, 8.7%). Auto-Ab positivity correlated with higher median HBsAg levels (<em>p</em> = 0.0110). All individuals with detectable anti-T1IFN auto-Abs were PegIFNα non-responders.</div></div><div><h3>Conclusions</h3><div>Non-neutralising anti-IFN auto-Abs are common in CHB and associate with higher median HBsAg levels. Further prospective study of anti-cytokine auto-Abs in CHB are required to characterise the association with long-term outcomes.</div></div><div><h3>Impact and implications</h3><div>HBV and PegIFNα individually may induce broad autoreactivity associated with dysregulated antiviral immune responses. Auto-Ab screening prior to PegIFNα treatment or other immunotherapies may play a critical role in predicting treatment responses.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101382"},"PeriodicalIF":9.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143815577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}