Hepatitis B virus persistence aggravates hepatic immunotolerance, leading to the failure of cell-intrinsic type I interferon and antiviral response.
However, whether and how Hepatitis B virus-induced hepatocyte-intrinsic tolerance influences systemic adaptive immunity has never been reported, which is becoming the major obstacle for chronic Hepatitis B virus therapy.
Dr Peixiang Lan and colleagues from China studied a Hepatitis B virus-persistent mouse, established by hydrodynamic injection of an Hepatitis B virus-genome-containing plasmid, exhibited not only hepatocyte-intrinsic but also systemic immunotolerance to Hepatitis B virus rechallenge.
The team reported that HBV-specific CD8+ T-cell and anti-HBs antibody generation were systemically impaired by HBV persistence in hepatocytes.
|CD8+ T cells play a critical role in clearance of Hepatitis B virus|
The researchers noted that Hepatitis B virus-induced hepatocyte-intrinsic immune tolerance was reversed when a dually functional vector containing both an immunostimulating single-stranded RNA and an HBx-silencing short hairpin RNA was administered, and the systemic anti-Hepatitis B virus adaptive immune responses, including CD8+ T-cell and anti-HBs antibody responses, were efficiently recovered.
During this process, CD8+ T cells and interferon-gamma secreted play a critical role in clearance of Hepatitis B virus.
However, when IFN-α/β receptor was blocked or the Toll-like receptor 7 signaling pathway was inhibited, the activation of CD8+ T cells and clearance of Hepatitis B virus was significantly impaired.
Dr Lan's team concludes, "These results suggest that recovery of HBV-impaired hepatocyte-intrinsic innate immunity by the dually functional vector might overcome systemic adaptive immunotolerance in an IFN-α- and toll like receptor 7-dependent manner."
"The strategy holds promise for therapeutic intervention of chronic persistent virus infection and associated cancers."