Abstract
Immune-suppression driven Hepatitis B Virus (HBV)-reactivation poses serious concerns since it occurs in several clinical settings and can result in severe forms of hepatitis. Previous studies showed that HBV strains, circulating in patients with HBV-reactivation, are characterized by an enrichment of immune-escape mutations in HBV surface antigen (HBsAg). Here, we focused on specific immune-escape mutations associated with the acquisition of N-linked glycosylation sites in HBsAg (NLGSs). In particular, we investigated profiles of NLGSs in 47 patients with immunosuppression-driven HBV-reactivation and we evaluated their impact on HBsAg-antigenicity and HBV-replication in vitro. At HBV-reactivation, despite a median serum HBV-DNA of 6.7 [5.3–8.0] logIU/mL, 23.4% of patients remained HBsAg-negative. HBsAg-negativity at HBV-reactivation correlated with the presence of >1 additional NLGSs (p < 0.001). These NLGSs are located in the major hydrophilic region of HBsAg (known to be the target of antibodies) and resulted from the single mutation T115N, T117N, T123N, N114ins, and from the triple mutant S113N+T131N+M133T. In vitro, NLGSs strongly alter HBsAg antigenic properties and recognition by antibodies used in assays for HBsAg-quantification without affecting HBsAg-secretion and other parameters of HBV-replication. In conclusion, additional NLGSs correlate with HBsAg-negativity despite HBV-reactivation, and hamper HBsAg-antigenicity in vitro, supporting the role of NGSs in immune-escape and the importance of HBV-DNA for a proper diagnosis of HBV-reactivation.
Highlights
Hepatitis B virus (HBV) reactivation is defined as the abrupt reappearance of HBV in the serum of a person with a previously resolved infection or a marked increase of HBV in an immunosuppressed patient with a previously stable chronic infection [1,2,3]
HBV-DNA compared to wt (p > 0.05) (Figure 1B–D). These results suggest that the introduction of the identified additional N-linked glycosylation sites did not alter the efficiency of HBV replication
This study shows that a not negligible were fraction of patients, negative to HBV surface antigen (HBsAg) and positive
Summary
Hepatitis B virus (HBV) reactivation is defined as the abrupt reappearance of HBV in the serum of a person with a previously resolved infection or a marked increase of HBV in an immunosuppressed patient with a previously stable chronic infection [1,2,3]. HBV reactivation occurs in a wide range of clinical settings characterized by different degrees of immunosuppression. The risk of HBV reactivation is related to the establishment of the HBV-DNA minichromosome named covalently closed circular. DNA (cccDNA) in hepatocytes during the early phases of HBV infection and to its persistence for a long time (potentially lifelong) after the clinical resolution of infection. An impairment of this control can allow cccDNA to enhance its activity and to start the reactivation phase. HBV reactivation can be clinically severe, resulting in death for acute liver failure or progressive liver disease and cirrhosis [1]
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