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Circulating serum HBsAg level is a biomarker for HBV-specific T and B cell responses in chronic hepatitis B patients.

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 (HBs^lo) or >50,000?IU/ml (HBs^hi) using immunological assays (flow cytometry, ICS, ELISPOT). HBs^hi 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 HBs^lo patients had IFN?⁺TNF?⁺ and IFN?⁺ IL2⁺ CD4⁺ T cell responses respectively, in comparison to 33% and 13% of HBs^hi patients. Checkpoint blockade with ?PD-1 improved HBV-specific CD4⁺ T cell function only in HBs^lo patients. HBsAg-specific antibody-secreting cells (ASCs) response was not different between these groups, yet ?PD-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.

SUBMITTER: Kim JH

PROVIDER: S-EPMC7000714 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Circulating serum HBsAg level is a biomarker for HBV-specific T and B cell responses in chronic hepatitis B patients.

Kim Jin Hyang JH Ghosh Alip A Ayithan Natarajan N Romani Sara S Khanam Arshi A Park Jang-June JJ Rijnbrand Rene R Tang Lydia L Sofia Michael J MJ Kottilil Shyam S Moore Chris B CB Poonia Bhawna B

Scientific reports 20200204 1

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 (HBs<sup>l ...[more]

PMID: 32020034

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Project description:As alternative indexes of hepatitis B virus (HBV), covalently closed circular DNA (cccDNA) transcriptional activity, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), and peripheral blood RNA known as pgRNA, have been advocated as novel serum markers for prediction of prognosis and treatment response in chronic hepatitis B (CHB). Since the availability of commercial quantitative assays of HBsAg in 2011, HBsAg has been widely used for predicting treatment response of patients with CHB. Patients who received interferon therapy have shown a sharper reduction of HBsAg level than those who received nucleoside drug (NAs) therapy. Upon peginterferon treatment, sustained responders have presented a larger reduction of HBsAg level than the non-responders. An absence of HBsAg decline, together with < 2log reduction in HBV DNA at week 12, can serve as a stopping rule in HBsAg-negative patients infected with genotype D HBV. A sharp reduction of HBsAg titer in the NAs therapy is a predictor of HBsAg clearance in long-term treatment. HBcrAg, which consists of three species of related proteins sharing an identical 149 amino acid sequence, including HbcAg, hepatitis B e antigen (HBeAg), and a truncated 22-kDa precore protein, is still detectable in situations where serum HBV DNA levels become undetectable or HBsAg loss is achieved. Therefore, HBcrAg remains a measurable serum marker to correlate with cccDNA in this situation. The decline in HBcrAg has been observed with NAs therapy and the pattern of decline might provide prognostic information on the risk of HBV post-treatment reactivation. Peripheral blood RNA, which is known as pgRNA, directly derives from cccDNA and reflects intrahepatic cccDNA level. Quantitative pgRNA has been suggested to be helpful in CHB management. However, commercial quantitative assays are lacking. Additionally, the use of simultaneous and continuous clearance of HBV RNA and HBV DNA in serum has been suggested to be a safe stopping rule of NAs therapy for patients with CHB. However, clinical studies of large sample sizes are needed to prove the feasibility and significance of using serum HBV RNA as the assessment standard of antiviral therapy in CHB and the safety of the stopping rule in clinics.

Dataset Information

Circulating serum HBsAg level is a biomarker for HBV-specific T and B cell responses in chronic hepatitis B patients.

Publications

Circulating serum HBsAg level is a biomarker for HBV-specific T and B cell responses in chronic hepatitis B patients.

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