Toward a Functional Cure for Hepatitis B: The Rationale and Challenges for Therapeutic Targeting of the B Cell Immune Response

Ma, Zhiyong; Zhang, Ejuan; Shicheng, Gao; Xiong, Yong; Lu, Mengji

doi:10.3389/fimmu.2019.02308

Cited by 40 publications

(27 citation statements)

References 130 publications

(147 reference statements)

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“…A small numbers of the study cohort showed co-existence of HBs Ag/Hbs Ab reactive probably on a transitional state to clear the virus or probably suggesting a selection of immune escape mutants during the disease period, a finding previously reported. 32,[34][35][36][37] Individuals with immune tolerance CHBV could not be identified within the study cohort, in agreement with recent reports that challenged the early concepts of existence of this immune pathologic phase. Recent evidence showed that subtle liver damage in the presence of normal aminotransferases levels exits in CHBV individuals.…”

Section: Discussionsupporting

confidence: 85%

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Untitled

2020

JHVRV

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Background: Hepatitis B virus (HBV) infection is an immune liver disease affecting millions worldwide. Despite availability of an efficacious vaccine, elimination of HBV infections is aloft. This study aimed to identify the immune-pathological phases of chronic HBV infection (CHBV) among Sudanese individuals to refine management strategies. Materials and methods: In a prospective cross-sectional study and following informed consent, 1593 individuals with HBs Ag reactivity were enrolled. Serum total protein/ albumin, ALT, AST, total bilirubin, HBs Ag/Ab, HBe Ag/Ab, HBc IgM/HBc total antibodies and HBV viral loads were measured. Results: Mean aminotransferase levels for HBs Ag-reactive individuals were significantly higher compared to apparently normal individuals, while the mean total protein and serum albumin were within normal ranges. The majority of HBs Ag-reactive individuals were reactive to total anti-HBc and HBe Ab, while concurrent HBe Ag/Ab reactivity was seen in a minority. Inactive carriers constituted the majority of HBs Ag reactive individuals, while the immune tolerance CHBV phase could not be identified. The reactivation phase had the highest viral load. Conclusion: inactive carrier state is the predominant immune-pathological phase among Chronic HBV Sudanese individuals. Regular follow ups and no oral anti-viral drug treatment as the management of choice to reduce cost, drug-associated toxicities and emergence of resistant strains.

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Section: Discussionsupporting

confidence: 85%

“…Recent evidence showed that subtle liver damage in the presence of normal aminotransferases levels exits in CHBV individuals. 10,32,[34][35][36][37]…”

Section: Discussionmentioning

confidence: 99%

Untitled

2020

JHVRV

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“… 1 The exact mechanism of how PEG-IFN promotes HBsAg clearance remains unknown, and studies on predictors of HBsAg loss are still in the exploratory stage. 9 – 11 However, there is accumulating evidence that PEG-IFN predominantly expands the NK cells compartment without boosting virus-specific T cells in HBV. 12 , 13 NK cells respond quickly to stimulants.…”

Section: Discussionmentioning

confidence: 99%

Contribution of NK cells to HBsAg seroconversion in inactive HBsAg carriers following pegylated IFN therapy

et al. 2020

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Our recent study showed a high rate of HBsAg seroconversion in inactive HBsAg carriers (IHCs) treated with pegylated IFN (PEG-IFN). To understand the immune-mediated component of the HBsAg seroconversion better, this study investigated the role of NK cells. A total of 44 IHCs were given 48 wk of PEG-IFN. Fifteen cases achieved HBsAg seroconversion (R group), whereas 29 failed (NR group). The proportion and activity (CD107α and IFN-γ production) of NK cells were measured before and during treatment. We found that the proportion of NK cells in the R group was higher than in the NR group at baseline and during PEG-IFN treatment, even when patients were matched for age, sex and treatment period. IFN- γ secretion and CD107α expression from NK cells in cases who achieved HBsAg seroconversion were significantly higher than patients matched for age, sex, HBsAg and treatment period in the NR group at baseline and during PEG-IFN treatment. We also found that in HBsAg seroconversion cases, NK cells activity increased after PEG-IFN treatment, especially before HBsAg seroconversion. These effects were not found in non-responders. In conclusion, we demonstrated that the increase of NK cells accompanied by enhanced activity during PEG-IFN treatment favoured HBsAg seroconversion for IHC, and that NK cells may play a role in HBV seroconversion.

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“…Recently, the function of HBV-specific B cells in HBV infection has been characterized by using fluorescently labeled HBV proteins, showing impairment in chronically infected patients (174)(175)(176). Modulation of B cell function and antibody production may represent another option for immunotherapy (87,177). A number of host genetic determinants have been identified to contribute to HBV control and pathogenesis (178).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

Zhao

Chen

2020

Front. Immunol.

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Functional cure" is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. "Functional cure" can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.

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Toward a Functional Cure for Hepatitis B: The Rationale and Challenges for Therapeutic Targeting of the B Cell Immune Response

Cited by 40 publications

References 130 publications

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Contribution of NK cells to HBsAg seroconversion in inactive HBsAg carriers following pegylated IFN therapy

Advances in Targeting the Innate and Adaptive Immune Systems to Cure Chronic Hepatitis B Virus Infection

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