Downregulation of HLA Class II Molecules by G1896A Pre-Core Mutation in Chronic Hepatitis B Virus Infection

Abstract

Over the past decade, increasing attention has been focused on the contribution of naturally occurring mutations in the hepatitis B virus (HBV) genome to the clinical course of the chronic infection. The aim of this study was to investigate the effect of the HBV pre-core mutation G1896A on the expression of HLA class II molecules and the core protein of hepatitis B in liver biopsies of chronic hepatitis B (CHB) infection. In 30 HBeAg-negative CHB patients the pre-core region of the HBV genome was amplified and sequenced to determine the presence of the mutation G1896A. Liver biopsies were scored based on the Histology Activity Index (HAI) system and immunohistochemistry (IHC) was performed to study the expression of HLA class II molecules on the antigen-presenting cells and the core protein in hepatocytes. We found that 19 of the 30 patients (63%) harbored the G1896A mutation. Compared to the patients without this mutation, those with G1896A had lower HAI scores (5.0 +/- 2.8 versus 7.9 +/- 4, p = 0.03). The study of the expression of HLA-II molecules in our patients revealed that subjects with the G1896A mutation had lower expression of HLA-II compared to wild-type infected subjects (1.87 +/- 0.6 versus 3.27 +/- 1.5, p < 0.01). Core protein expression was present in four patients (13.3%) who had higher HBV DNA levels than patients without core protein expression (3.81 +/- 0.78 versus 2.02 +/- 0.16, p < 0.001). These results suggest that the G1896A pre-core mutation may directly interfere with antigen presentation, most likely by decreasing the availability of HLA class II molecules, and this may result in less aggressive liver disease in HBeAg-negative CHB infection.

Clinical Feature of Intrahepatic B-Lymphocytes in Chronic Hepatitis B

“…The pathogenesis of HBV-related chronic liver disease is not well understood. However, it is clear that the immune mechanisms associated with the antiviral response are responsible for CHB outcome [2–4]. The existence of lymphocytes in the human liver is representing a pathological situation [5].…”

The Possible Role of TLR2 in Chronic Hepatitis B Patients with Precore Mutation

“…The reason that precore negative mutants become predominant in some patients during chronic hepatitis B infection is not clear. However, the host immune system has a functional role in the selection of precore mutant strains of HBV, and their appearance might reflect immunological control of infection [7, 8]. …”

Hepatitis B Virus Adaptation to the CD8+ T Cell Response: Consequences for Host and Pathogen

“…Interestingly, these studies are three decades old and have not been replicated in the more recent literature. Downregulation of HLA class II molecules by pre-core mutants has also been described during chronic HBV infection ( 102 ). Mutations altering the processing or presentation of HBV HLA class I epitopes, although not conclusively demonstrated, could hypothetically be relevant for escape from the CD8+ T cell-mediated immune response in human infection (Figure 3 , box 2).…”