Hepatitis B virus replication could enhance regulatory T cell activity by producing soluble heat shock protein 60 from hepatocytes

Background. HBcAg-specific regulatory T (T_reg) cells play an important role in the pathogenesis of chronic hepatitis B. Soluble heat shock proteins, especially soluble heat shock protein 60 (sHSP60), could affect the function of T_reg cells via Toll-like receptor. Methods. We analyzed the relationship between soluble heat shock protein production and hepatitis B virus (HBV) replication with both clinical samples from HBeAg-positive patients with chronic hepatitis B (n=24) and HBeAb-positive patients with chronic hepatitis B (n=24) and in vitro HBV-replicating hepatocytes. Thereafter, we examined the biological effects of sHSP60 with isolated T_reg cells. Results. The serum levels of sHSP60 in patients with chronic hepatitis B were statistically significantly higher than those in patients with chronic hepatitis C (P < .01), and the levels of sHSP60 were correlated with the HBV DNA levels (R=0.532; P < .001) but not with the alanine aminotransferase levels. Moreover, the levels of sHSP60 in HBV-replicating HepG2 cells were statistically significantly higher than those in control HepG2 cells. Preincubation of CD4⁺ CD25⁺ cells with recombinant HSP60 (1 ng/mL) statistically significantly increased the frequency of HBcAg-specific interleukin 10-secreting T_reg cells. The frequency of IL7R ^-CD4⁺CD25⁺ cells, the expression of Toll-like receptor 2, and the suppressive function of T_reg cells had declined during entecavir treatment. Conclusion. The function of HBcAg-specific T _reg cells was enhanced by sHSP60 produced from HBV-infected hepatocytes. Entecavir treatment suppressed the frequency and function of T _reg cells; this might contribute to the persistence of HBV infection.