Abstract
Chronic hepatitis B (CHB) infection functional cure is defined as sustained loss of HBsAg and several therapeutic strategies are in clinical development designed to pharmacologically reduce serum HBsAg, break immune tolerance, and increase functional cure rates. However, little is known about pre-treatment HBsAg levels as an indicator of HBV immune potential. Here, we compared the phenotypes and HBV-specific response of lymphocytes in CHB patients stratified by serum HBsAg levels <500 (HBslo) or >50,000 IU/ml (HBshi) using immunological assays (flow cytometry, ICS, ELISPOT). HBshi patients had significantly higher expression of inhibitory PD-1 on CD4+ T cells, particularly among TEMRA subset, and higher FcRL5 expression on B cells. Upon HBcAg(core) or HBsAg(env)-stimulation, 85% and 60% of HBslo patients had IFNγ+TNFα+ and IFNγ+ IL2+ CD4+ T cell responses respectively, in comparison to 33% and 13% of HBshi patients. Checkpoint blockade with αPD-1 improved HBV-specific CD4+ T cell function only in HBslo patients. HBsAg-specific antibody-secreting cells (ASCs) response was not different between these groups, yet αPD-1 treatment resulted in significantly higher fold change in ASCs among patients with HBsAg <100 IU/ml compared to patients with HBsAg >5,000 IU/ml. Thus, serum HBsAg correlates with inhibitory receptor expression, HBV-specific CD4+ T cell responses, and augmentation by checkpoint blockade.
Highlights
Chronic hepatitis B (CHB) infection functional cure is defined as sustained loss of HBsAg and several therapeutic strategies are in clinical development designed to pharmacologically reduce serum HBsAg, break immune tolerance, and increase functional cure rates
The current standard of care, including nucleot(s)ide analogue (NA) or peg-IFN fails to achieve the recommended curative endpoint in the majority of CHB patients despite long duration of treatment[1,2]. This is because the current first-line therapy does little to remove circulating HBsAg driven by transcriptional activity of covalently closed circular DNA in infected hepatocytes, despite DNA suppression, ALT normalization in HBeAg-negative patients, and HBeAg loss in HBeAg-positive patients[1,3]
Further analysis of memory T cell subsets based on CCR7 and CD45RO expression showed no significant difference in the proportions of the naïve, central memory (CM), effector memory (EM) or terminally differentiated effector T cells (EMRA) between the HBshi and HBslo groups (Fig. 1C)
Summary
Chronic hepatitis B (CHB) infection functional cure is defined as sustained loss of HBsAg and several therapeutic strategies are in clinical development designed to pharmacologically reduce serum HBsAg, break immune tolerance, and increase functional cure rates. Studies addressing the relationship between serum HBsAg levels and HBV-specific immune responses would provide further insights on the immunobiology of HBV and help interpret upcoming clinical trial data It is unknown whether HBsAg removal alone will be enough to induce HBV immune control or whether additional immune activation are required to achieve functional cure. While definitive evidences as to whether serum HBsAg levels can be a direct correlate of the immune functions of CHB patients have been lacking, a few studies have addressed the relationship between viral components and specific immune parameters. We evaluated if the functional response of lymphocytes to immune checkpoint blockade could be differentiated by serum HBsAg levels
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