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Therapeutic recovery of HBV-induced hepatocyte-intrinsic immune defect

Therapeutic recovery of hepatitis B virus (HBV)-induced hepatocyte-intrinsic immune defect reverses systemic adaptive immune tolerance

News image

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
Hepatology

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."

Hepatol 2013: 58(1): 73–85
25 July 2013

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