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Individuals who are chronically infected with the hepatitis B virus (HBV) are highly heterogenous with respect to serum levels of HBV DNA, HBV particles and viral proteins. Since circulating leukocytes, such as monocytes, are constantly exposed to these viral components, it is likely that the functionality of these cells is affected. However, at present, little information is available on the consequences of the interaction between monocytes and viral components. Therefore, we examined the in vitro effects of HBV surface antigen (HBsAg) on monocytes and evaluated whether these effects were reflected in vivo. We observed that in vitro HBsAg exposure of monocytes induced robust production of IL-6 and TNF. However, between chronic HBV patients with distinct levels of serum HBsAg, HBV early antigen (HBeAg), and HBV DNA, TLR-induced monocyte cytokine production did not differ. Importantly, HBsAg-induced cytokine production by monocytes was similar between patients and healthy controls showing that earlier in vivo exposure to HBsAg does not affect the in vitro response. Additionally, we show that IL-10 is able to inhibit cytokine production by HBsAg-induced monocytes. In conclusion, we demonstrate that monocytes can recognize and respond to HBsAg, resulting in vigorous pro-inflammatory cytokine production in vitro. However, phenotype and function of the monocyte compartment in chronic HBV patients are not influenced by differences in levels of serum viral components, suggesting that regulatory mechanisms are active to avoid excessive in vivo monocyte activation. [ABSTRACT FROM AUTHOR]

Systems biology has proven to be a powerful tool to identify reliable predictors of treatment response in chronic hepatitis C virus (HCV) infection. In the present study, we studied patients with chronic HCV infection who responded to interferon (IFN)-based therapy, as evidenced by an absence of HCV RNA at the end of treatment, and focused on two issues that have not received much attention. First, we evaluated whether specific genes or gene expression patterns in blood were able to distinguish responder patients with a viral relapse from responder patients who remained virus negative after cessation of treatment. We found that patients with chronic HCV infection who were sustained responders and relapsers after IFN-based therapy showed comparable baseline clinical parameters and immune compositions in blood. However, at baseline, the gene expression profiles of a set of 18 genes predicted treatment outcome with an accuracy of 94%. Second, we examined whether patients with successful therapyinduced clearance of HCV still exhibited gene expression patterns characteristic of HCV or whether normalization of their transcriptome was observed. We observed that the relatively high expression levels of IFN-stimulated genes (ISGs) in patients with chronic HCV infection prior to therapy were reduced after successful IFN-based antiviral therapy (at 24 weeks of follow-up). These ISGs included the CXCL10, OAS1, IFI6, DDX60, TRIM5, and STAT1 genes. In addition, 1,428 differentially expressed non-ISGs were identified in paired pre- and posttreatment samples from sustained responders, which included genes involved in transforming growth factor beta (TGF-β) signaling, apoptosis, autophagy, and nucleic acid and protein metabolism. Interestingly, 1,424 genes with altered expression levels in responder patients after viral eradication were identified, in comparison to normal expression levels in healthy individuals. Additionally, aberrant expression levels of a subset of these genes, including the interleukin-32 (IL-32), IL-16, CCND3, and RASSF1 genes, were also observed at baseline. Our findings indicate that successful antiviral therapy for patients with chronic HCV infection does not lead to normalization of their blood transcriptional signature. The altered transcriptional activity may reflect HCV-induced liver damage in previously infected individuals. [ABSTRACT FROM AUTHOR]

Background & Aims: HBsAg secretion may impact immune responses to chronic HBV infection. Thus, therapeutic approaches to suppress HBsAg production are being investigated. Our study aims to examine the immunomodulatory effects of high and low levels of circulating HBsAg and thereby improve our understanding of anti-HBV immunity., Methods: An optimized 10x Genomics single-cell RNA sequencing workflow was applied to blood samples and liver fine-needle aspirates from 18 patients undergoing tenofovir/entecavir (NUC) treatment for chronic HBV infection. They were categorized based on their HBsAg levels: high (920-12,447 IU/ml) or low (1-100 IU/ml). Cluster frequencies, differential gene expression, and phenotypes were analyzed., Results: In the blood of HBV-infected patients on NUC, the proportion of KLRC2 + "adaptive" natural killer (NK) cells was significantly lower in the HBsAg-high group and, remarkably, both KLRC2 + NK and KLRG1+ CD8 T cells display enrichment of lymphocyte activation-associated gene sets in the HBsAg-low group. High levels of HBsAg were associated with mild immune activation in the liver. However, no suppression of liver-resident CXCR6+ NCAM1+ NK or CXCR6+ CD69+ CD8 T cells was detected, while memory B cells showed signs of activation in both the blood and liver., Conclusions: Among NUC-treated patients, we observed a minimal impact of HBsAg on leukocyte populations in the blood and liver. However, for the first time, we found that HBsAg has distinct effects, restricted to NK-, CD8 T-, and memory B-cell subsets, in the blood and liver. Our findings are highly relevant for current clinical studies evaluating treatment strategies aimed at suppressing HBsAg production and reinvigorating immunity to HBV., Impact and Implications: This study provides unique insight into the impact of HBsAg on gene expression levels of immune cell subsets in the blood and liver, particularly in the context of NUC-treated chronic HBV infection. It holds significant relevance for current and future clinical studies evaluating treatment strategies aimed at suppressing HBsAg production and reinvigorating immunity to HBV. Our findings raise questions about the effectiveness of such treatment strategies and challenge the previously hypothesized immunomodulatory effects of HBsAg on immune responses against HBV., Competing Interests: A.B. received grants not related to this project from Gilead Sciences, Fujirebio, GlaxoSmithKline, and Janssen Pharma. R.J.K. received grants from GlaxoSmithKline, Janssen-Cilag, and Echosens (not related to this project), and received consulting fees, payments or honoraria for lectures, presentations, or other educational events from AbbVie, Echosens, and Gilead Sciences. All remaining authors declare that they have no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Objective: We report the immune response during a case of acute HEV response in a patient with an acute hepatitis E virus (HEV) genotype 3 infection in the Netherlands., Methods: Cytokine evaluation was performed via multiplex cytokine array for 65 immune markers in plasma during the different phases of hepatitis., Results: The patient initially presented with features typical of acute viral hepatitis, with detectable HEV RNA in blood. This evolved into a cholestatic disease following peripheral clearance of the virus, leading to the demise of the patient. Real time PCR revealed the presence of HEV in liver tissue, suggestive of active intrahepatic infection despite clearance in blood. During the phase of detectable HEV RNA in serum, there was a surge in T-cell-related immune mediators, as well as interferon alpha and interferon gamma-induced protein 10 (IP-10), characteristic of a viral infection. After clearance of the virus in the blood and development of cholestatic hepatitis, several inflammatory markers subsided, followed by an increase in immune factors related to anti-inflammatory activity, as well as monocyte/macrophage-related markers, likely due to the intrahepatic presence of the virus., Conclusions: This report describes the dissociation of intra- and extra-hepatic immune responses during acute HEV infection. As shedding of the virus became solely intrahepatic, an immune profile reflective of the activity of hepatic resident cells was observed., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Concern has arisen about the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection treated with direct-acting antivirals (DAAs). To identify patients at risk for HCC, we evaluated serum levels of immune mediators before, during, and after DAA treatment of HCV infection. Our study included 13 patients who developed HCC within 18 months after treatment (3 with HCC recurrence and 10 with new HCC) and 10 patients who did not develop HCC (controls), within at least 24 months of treatment (median, 26 months). We identified a set of 12 immune mediators (cytokines, growth factors, and apoptosis markers) whose levels were significantly higher in serum before DAA treatment of patients who eventually developed de novo HCC compared with controls. A panel of 9 cytokines, measured in serum before treatment (MIG, IL22, TRAIL, APRIL, VEGF, IL3, TWEAK, SCF, IL21), identified patients who developed de novo HCC with an area under the receiver operating characteristic curve value higher than 0.8. Further analyses of changes in levels of inflammatory cytokines during DAA treatment also provides important information about HCV-induced carcinogenesis and the effects of DAAs., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Sustained immune activation during chronic HIV infection is considered to augment co-morbidity and mortality. Effective combination antiretroviral therapy (cART) has shown to dampen immune activation especially during the first year cART, but the effects of long-term cART in patients without major comorbidities remains under-investigated. We performed a comprehensive analysis including cellular, intracellular and plasma biomarkers to study the effect of cART on immune parameters in 5 groups of 10 HIV patients. All patients were without major co-morbidities and grouped based on cART duration (0, 1, 3, 5, and 10 years). We included 10 matched healthy controls for comparison. Our data show that after the first year of cART, no additional effect on the level of inflammatory markers is observed in HIV infected patients without major co morbidities. Residual immune activation status in well-treated HIV-infection is similar to levels observed in healthy controls., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)