Abstract
Hepatitis B virus (HBV) reactivation and recurrence are common in patients under immunosuppression and can be controlled by hepatitis B immunoglobulin, antivirals, and hepatitis B vaccine. However, the detailed analysis of HBV infection under immunosuppression is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV replication and T cell responses were analyzed in a HBV-transfected mouse model under immunosuppressive therapy. During the treatment, HBV replication was at a high level in mice treated with dexamethasone, cyclosporine, and cyclophosphamide, whereas was terminated in mice treated with mycophenolate mofetil. After the withdrawal, HBV replication was at low or high levels in the dexamethasone-treated mice or in both cyclosporine- and cyclophosphamide-treated mice. The early withdrawal of cyclosporine allowed the recovery of suppressed T cell responses and led to subsequent HBV clearance, while the adoptive immune transfer to the mice with HBV persistence led to HBV suppression. Taken together, long-term HBV persistence under immunosuppression depends on the immunosuppressive drugs used and on the treatment duration and is mediated by the suppressed intrahepatic CD8 T cell response. These data may be helpful for individualized immunosuppressive therapy in patients with high risk of HBV reactivation and recurrence, and the mouse system is suitable for studying HBV reactivation and recurrence under immunosuppression.
Highlights
Hepatitis B virus (HBV) infection is widely distributed throughout the world
Hepatitis B virus surface antigen (HBsAg) and HBV DNA in sera from mice treated with DEX, CsA, or CYP maintained at the high levels of approximately 100 cut off index (COI) and 106– 7 copies/ml, respectively
The HBV replication in the BALB/c mice usually ceased within a few weeks, the HBV DNA became negative within 4 weeks, and the HBsAg was eliminated within 6 weeks in mice treated with saline (Fig. 1A)
Summary
Hepatitis B virus (HBV) infection is widely distributed throughout the world. At least 350 million people are HBV carriers and are at high risk for developing hepatic decompensation, cirrhosis, and hepatocellular carcinoma [1]. Strong and polyclonal CD8+ and CD4+ T cell responses are essential for the clearance of HBV infections from the liver[2]; patients receiving immunosuppressive therapy may have a potential high risk for HBV infection due to the lack of adequate immunity. HBV recurrence after liver transplantation occurs in 80–100% of patients without any prevention, while only occurring in up to 6.1% of patients after prophylactic treatment using hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogs (NAs) [4]. HBIG, NAs, and the hepatitis B vaccine are effective for preventing and treating HBV reactivation and recurrence, many factors remain unresolved. Patients under immunosuppressive therapy have poor response rates to the hepatitis B vaccine [5,6], and the strategies for the prophylaxis and treatment of HBV reactivation and recurrence should be optimized. Detailed analysis of the HBV infection under immunosuppression is essential for resolving the above-mentioned problems
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