Antigen Load and T Cell Function: A Challenging Interaction in HBV Infection

Montali, Ilaria; Vecchi, Andrea; Rossi, Marzia; Tiezzi, Camilla; Penna, Amalia; Reverberi, Valentina; Laccabue, Diletta; Missale, Gabriele; Boni, Carolina; Fisicaro, Paola

doi:10.3390/biomedicines10061224

Cited by 7 publications

(3 citation statements)

References 72 publications

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“…HBcrAg optimally discriminates between HBeAg(−) chronic hepatitis B and HBeAg-negative chronic HBV infection ( 20 – 22 ) but also could stratify the risk of fibrosis progression in patients with intermediate viral load ( 23 ). Both HBsAg and HBcrAg data suggest that the level of HBV antigenemia might determine the progression of liver damage in HBeAg-negative chronic HBV infection, and this fact could be linked to the effect of antigen load on T-cell function ( 24 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

HBsAg level defines different clinical phenotypes of HBeAg(−) chronic HBV infection related to HBV polymerase-specific CD8+ cell response quality

Peña-Asensio,

Calvo-Sánchez,

Miquel-Plaza

et al. 2024

Front. Immunol.

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BackgroundHBe-antigen(Ag)-negative chronic hepatitis B virus (HBV) infection is characterized by little liver fibrosis progression and vigorous HBV-multispecific CD8+ T-cell response.AimsTo assess whether HBsAg level could discriminate different HBeAg-negative chronic HBV infection subtypes with dissimilar quality of HBV-specific CD8+ T-cell response.MethodsWe recruited 63 HBeAg-negative chronic HBV infection patients in which indirect markers of liver inflammation/fibrosis, portal pressure, viral load (VL), and HBV-specific CD8+ cell effector function were correlated with HBsAg level.ResultsA positive linear trend between HBsAg level and APRI, liver stiffness (LS), liver transaminases, and HBV VL, and a negative correlation with platelet count were observed. Frequency of cases with HBV-specific CD8+ T-cell proliferation against at least two HBV epitopes was higher in HBsAg < 1,000 IU/ml group. CD8+ T-cell expansion after HBVpolymerase456-63-specific stimulation was impaired in HBsAg > 1,000 IU/ml group, while the response against HBVcore18-27 was preserved and response against envelope183-91 was nearly abolished, regardless of HBsAg level. Cases with preserved HBVpolymerase456-63 CD8+ cell response had lower LS/duration of infection and APRI/duration of infection rates. HBV-polymerase456-63-specific CD8+ T-cell proliferation intensity was negatively correlated with LS/years of infection ratio.ConclusionHBsAg > 1,000 IU/ml HBeAg-negative chronic HBV infection group shows indirect data of higher degree of inflammation, liver stiffness, and fibrosis progression speed, which are related to an impaired HBV-polymerase-specific CD8+ T-cell response.

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Section: Discussionmentioning

confidence: 99%

HBsAg level defines different clinical phenotypes of HBeAg(−) chronic HBV infection related to HBV polymerase-specific CD8+ cell response quality

Peña-Asensio,

Calvo-Sánchez,

Miquel-Plaza

et al. 2024

Front. Immunol.

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“…Patients with chronic HBV infection have impaired innate and adaptive immune responses to HBV. Persistently high viral antigen levels had been incriminated to result in the exhaustion of HBV-specific T cells 15 and possibly dendritic cells and natural killer (NK) cells. 16 , 17 The recovery of HBV-specific immune responses had been demonstrated in patients with spontaneous, IFNα-induced or NA-induced HBeAg or HBsAg loss.…”

Section: Barriers To Hbv Curementioning

confidence: 99%

What will it take to cure hepatitis B?

Jeng

Lok

2023

Hepatology Communications

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The current treatment of chronic HBV infection, pegylated interferon-α (pegIFNα) and nucleos(t)ide analog (NA), can suppress HBV replication, reverse liver inflammation and fibrosis and reduce the risks of cirrhosis, HCC, and HBV-related deaths, but relapse is common when the treatment is stopped before HBsAg loss. There have been major efforts to develop a cure for HBV, defined as sustained HBsAg loss after a finite course of therapy. This requires the suppression of HBV replication and viral protein production and the restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. Immune modulatory therapies to stimulate adaptive or innate immunity and/or to remove immune blockade are being tested. NAs are included in most and pegIFNα in some regimens. Despite the combination of 2 or more therapies, HBsAg loss remains rare in part because HbsAg can be derived not only from the covalently closed circular DNA but also from the integrated HBV DNA. Achievement of a functional HBV cure will require therapies to eliminate or silence covalently closed circular DNA and integrated HBV DNA. In addition, assays to differentiate the source of circulating HBsAg and to determine HBV immune recovery, as well as standardization and improvement of assays for HBV RNA and hepatitis B core-related antigen, surrogate markers for covalently closed circular DNA transcription, are needed to accurately assess response and to target treatments according to patient/disease characteristics. Platform trials will allow the comparison of multiple combinations and channel patients with different characteristics to the treatment that is most likely to succeed. Safety is paramount, given the excellent safety profile of NA therapy.

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“…5 Barriers to functional cure include the high load of HBV antigens (e.g., HBsAg) coming from persistent HBV covalently closed circular DNA or integrated HBV genomes, impaired immune responses associated with exhausted T-cell reactivity, and the immune-tolerant environment of the liver. [7][8][9] Stimulating pattern recognition receptors such as toll-like receptors (TLRs) can induce innate and adaptive immune responses, and TLRs represent a potential therapeutic target. [10][11][12] TLR7 is expressed on, and agonists directly stimulate, plasmacytoid dendritic cells (pDCs), B cells, and various cells in the liver (Kupffer cells, liver sinusoidal endothelial cells, and hepatic stellate cells).…”

Section: Introductionmentioning

confidence: 99%

A single, oral dose of the TLR7 agonist JNJ-64794964 induces transcriptomic and phenotypic changes in peripheral immune cells in healthy adults

et al. 2023

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Background Chronic hepatitis B (CHB) is responsible for major disease burden worldwide. However, the number of available therapies is limited; cure remains an elusive goal. JNJ-64794964 (JNJ-4964) is an oral toll-like receptor-7 (TLR7) agonist being evaluated for the treatment of CHB. Here, we investigated the capacity of JNJ-4964 to induce transcriptomic and immune cell changes in peripheral blood in healthy volunteers. Methods Peripheral blood was collected in the JNJ-4964 first-in-human phase 1 trial at multiple time points to assess transcriptomics and changes in frequency and phenotype of peripheral-blood mononuclear cells. Correlation of changes to JNJ-4964 exposure (Cmax) and changes in cytokine levels (C-X-C motif chemokine ligand 10 [CXCL10] and interferon alpha [IFN-α]) were evaluated. Results Fifty-nine genes, mainly interferon-stimulated genes, were up-regulated between 6 hours and 5 days after JNJ-4964 administration. JNJ-4964 increased frequencies of CD69, CD134, CD137, and/or CD253-expressing natural killer (NK) cells, indicative of NK cell activation. These changes correlated with Cmax, increase of CXCL10, and induction of IFN-α and were observed at IFN-α levels that are associated with no/acceptable flu-like adverse events. JNJ-4964 administration resulted in increased frequencies of CD86-expressing B cells, indicative of B-cell activation. These changes were predominantly observed at high IFN-α levels, which are associated with flu-like adverse events. Conclusions JNJ-4964 administration led to changes in transcriptional profiles and immune cell activation phenotype, particularly for NK cells and B cells. Together, these changes could represent a set of biomarkers for the characterization of the immune response in CHB patients receiving TLR7 agonists.

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Antigen Load and T Cell Function: A Challenging Interaction in HBV Infection

Cited by 7 publications

References 72 publications

HBsAg level defines different clinical phenotypes of HBeAg(−) chronic HBV infection related to HBV polymerase-specific CD8+ cell response quality

HBsAg level defines different clinical phenotypes of HBeAg(−) chronic HBV infection related to HBV polymerase-specific CD8+ cell response quality

What will it take to cure hepatitis B?

A single, oral dose of the TLR7 agonist JNJ-64794964 induces transcriptomic and phenotypic changes in peripheral immune cells in healthy adults

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