Hepatitis B functional cure and immune response

Zheng, Jia-Rui; Wang, Zilong; Feng, Bo

doi:10.3389/fimmu.2022.1075916

Cited by 19 publications

(21 citation statements)

References 148 publications

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“…Several studies have demonstrated that baseline quantitative HBsAg < 1,500 IU/ml can effectively predict HBsAg loss after a finite course of IFN-based therapy ( 27 , 28 ). However, HBsAg alone as a predictor could not fully predict the efficacy ( 15 , 29 ) nor reflect the liver’s immune status ( 30 ). Cytokines in serum can indirectly reflect intrahepatic immune response and inflammation ( 10 ).…”

Section: Discussionmentioning

confidence: 99%

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Serum cytokine change profile associated with HBsAg loss during combination therapy with PEG-IFN-α in NAs-suppressed chronic hepatitis B patients

et al. 2023

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ObjectiveThe aim of this study was to explore the profile of cytokine changes during the combination therapy with pegylated interferon alpha (PEG-IFN-α) and its relationship with HBsAg loss in nucleos(t)ide analogs (NAs)-suppressed chronic hepatitis B patients.MethodsSeventy-six patients with chronic hepatitis B with HBsAg less than 1,500 IU/ml and HBV DNA negative after receiving ≥ 1-year NAs therapy were enrolled. Eighteen patients continued to take NAs monotherapy (the NAs group), and 58 patients received combination therapy with NAs and PEG-IFN-α (the Add-on group). The levels of IFNG, IL1B, IL1RN, IL2, IL4, IL6, IL10, IL12A, IL17A, CCL2, CCL3, CCL5, CXCL8, CXCL10, TNF, and CSF2 in peripheral blood during treatment were detected.ResultsAt week 48, 0.00% (0/18) in the NAs group and 25.86% (15/58) in the Add-on group achieved HBsAg loss. During 48 weeks of combined treatment, there was a transitory increase in the levels of ALT, IL1RN, IL2, and CCL2. Compared to the NAs group, CXCL8 and CXCL10 in the Add-on group remain higher after rising, yet CCL3 showed a continuously increasing trend. Mild and early increases in IL1B, CCL3, IL17A, IL2, IL4, IL6, and CXCL8 were associated with HBsAg loss or decrease >1 log, while sustained high levels of CCL5 and CXCL10 were associated with poor responses to Add-on therapy at week 48.ConclusionsThe serum cytokine change profile is closely related to the response to the combination therapy with PEG-IFN-α and NAs, and may help to reveal the mechanism of functional cure and discover new immunological predictors and new therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

“…In CHB, Th1/Th2 and Th17/Treg were in immune imbalance ( 30 , 38 , 39 ), and antiviral treatment partially restored immune cell function ( 30 ). IL2 (Th1 cytokine) activated CD8+T cells and NK cells and promoted their proliferation and cytosolic activity ( 40 – 42 ).…”

Section: Discussionmentioning

confidence: 99%

Serum cytokine change profile associated with HBsAg loss during combination therapy with PEG-IFN-α in NAs-suppressed chronic hepatitis B patients

et al. 2023

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“…In contrast, mice treated with control siRNA (that therefore maintained high levels of HBV antigenemia) followed by therapeutic vaccination did not all cleared HBV antigenemia despite strong induction of CD4 Tfh and TCR clonal expansions. Given that the main difference with the group that cleared HBV was a more modest plasma cell clonal expansion, it suggests that mounting a CD4 Tfh response alone is not sufficient for clearing HBV and that induction of B-cells is a key factor (33).…”

Section: Discussionmentioning

confidence: 99%

Sustained liver HBsAg loss and clonal T and B cell expansion upon therapeutic DNA vaccination require low HBsAg levels

Conceição-Neto,

Pierson,

Vacca

et al. 2023

Preprint

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Background & AimsSuppression of HBV DNA, inhibition of HBsAg production and therapeutic vaccination to reverse HBV-specific T-cell exhaustion in chronic HBV patients are likely required to achieve functional cure. In the AAV-HBV mouse model, therapeutic vaccination can be effective in clearing HBsAg when hepatitis B surface (HBsAg) levels are low. The factor(s) required for mounting an effective immune control of HBV infection are unclear. Using a single-cell approach, we investigated the liver immune environment in the context of different levels of HBsAg as well as upon sustained HBsAg loss through treatment with an HBV specific GalNAc-siRNA followed by therapeutic vaccination.MethodsC57BL/6 mice were transduced with a range of rAAV-HBV DNA to express different HBsAg levels. Mice were treated with GalNAc-siRNA targeting HBV transcripts to lower the HBsAg levels and then vaccinated 4 times with a DNA vaccine encoding HBV Core, Pol and Surface. We used single-cell RNA-sequencing on homogenised liver resident cells, paired with single-cell V(D)J receptor sequencing to understand the changes in the liver immune microenvironment.ResultsTreatment with GalNAc-HBV siRNA followed by therapeutic vaccination, achieved a sustained HBsAg loss in all mice. This was accompanied by an induction of CD4 follicular helper T-cell responses, polyclonal activation of CD8 T-cells in the liver and clonal expansion of plasma cells that were responsible for antibody production.ConclusionsThis study provides novel insight into the immune changes in the liver at the single-cell level, highlighting the correlation between the induced reduction in HBsAg levels and the clonal expansion of CD4 follicular helper T-cells, CD8 cytotoxic T-cells, plasma cells, and ISG-producing neutrophils in the liver upon HBV siRNA and subsequent therapeutic vaccine treatment.Lay SummaryChronic hepatitis B infection is characterized by a complex interplay between immune responses and viral replication in the liver. To achieve functional cure a combination of different treatments is likely required. In this study single-cell approach was used to understand the liver microenvironment in the context of different HBsAg levels followed by therapeutic vaccination in AAV-HBV mouse model and to identify key factors required to achieve functional cure.Graphical abstractHighlightsAAV-HBV transduced mice sequentially treated with GalNAc-siRNA and therapeutic vaccine showed sustained HBsAg loss.The sustained HBsAg loss correlates with increased proportion and clonal expansion of CD4 follicular helper T-cells, CD8 cytotoxic T-cells, plasma cells, and ISG producing neutrophils in the liver.Baseline levels of HBsAg are important to determine outcome of therapeutic vaccination in mice.

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“…Granulocytes, dendritic cells (DCs), macrophages, mast cells, and natural killer (NK) cells play crucial roles as effector cells in various biological processes. The initiation of an effective innate immune response typically occurs when pathogen-associated molecular pattern (PAMP) molecules interact with pattern recognition receptors (PRRs)[ 24 , 25 ]. This interaction triggers the production of chemokines and pro-inflammatory cytokines and the activation of innate immune cells.…”

Section: Possible Immunological Mechanisms Of Hbv Reactivationmentioning

confidence: 99%

“…It is of utmost significance that the implementation of efficient anti-viral medication has the potential to impede the advancement of liver fibrosis and Cirrhosis, offering a pivotal means of managing individuals who are susceptible to severe liver disease resulting from HBV reactivation[ 115 , 116 ]. In addition to their anti-viral properties, the immunomodulatory capacities of NAs, as revealed by Zheng et al [ 25 ], are involved in regulating immunological reactions during the reactivation of HBV. Nucleic acid-based therapies have been observed to lower viral load, reducing viral antigen exposure effectively.…”

Section: Management Strategies For Hbv Reactivationmentioning

confidence: 99%

Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies

Ma,

Yan,

et al. 2024

World J Gastroenterol

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Hepatitis B virus (HBV) reactivation is a clinically significant challenge in disease management. This review explores the immunological mechanisms underlying HBV reactivation, emphasizing disease progression and management. It delves into host immune responses and reactivation’s delicate balance, spanning innate and adaptive immunity. Viral factors’ disruption of this balance, as are interactions between viral antigens, immune cells, cytokine networks, and immune checkpoint pathways, are examined. Notably, the roles of T cells, natural killer cells, and antigen-presenting cells are discussed, highlighting their influence on disease progression. HBV reactivation’s impact on disease severity, hepatic flares, liver fibrosis progression, and hepatocellular carcinoma is detailed. Management strategies, including anti-viral and immunomodulatory approaches, are critically analyzed. The role of prophylactic anti-viral therapy during immunosuppressive treatments is explored alongside novel immunotherapeutic interventions to restore immune control and prevent reactivation. In conclusion, this comprehensive review furnishes a holistic view of the immunological mechanisms that propel HBV reactivation. With a dedicated focus on understanding its implications for disease progression and the prospects of efficient management strategies, this article contributes significantly to the knowledge base. The more profound insights into the intricate interactions between viral elements and the immune system will inform evidence-based approaches, ultimately enhancing disease management and elevating patient outcomes. The dynamic landscape of management strategies is critically scrutinized, spanning anti-viral and immunomodulatory approaches. The role of prophylactic anti-viral therapy in preventing reactivation during immunosuppressive treatments and the potential of innovative immunotherapeutic interventions to restore immune control and proactively deter reactivation.

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Hepatitis B functional cure and immune response

Cited by 19 publications

References 148 publications

Serum cytokine change profile associated with HBsAg loss during combination therapy with PEG-IFN-α in NAs-suppressed chronic hepatitis B patients

Serum cytokine change profile associated with HBsAg loss during combination therapy with PEG-IFN-α in NAs-suppressed chronic hepatitis B patients

Sustained liver HBsAg loss and clonal T and B cell expansion upon therapeutic DNA vaccination require low HBsAg levels

Overview of the immunological mechanisms in hepatitis B virus reactivation: Implications for disease progression and management strategies

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