Granzyme H of Cytotoxic Lymphocytes Is Required for Clearance of the Hepatitis B Virus through Cleavage of the Hepatitis B Virus X Protein

Haidong, T. et al. J Immunol. 2012. 188: 824-831

Speaker: Chin Kun Tsai (蔡進焜)                           Time: 13:00~14:00, May.2, 2012

Commentator: Dr. Yao Chang (張堯老師)            Place: Room 601

Abstract

Cytotoxic lymphocytes eliminate intracellular pathogens via granule exocytosis pathway¹. This pathway contains pore-forming perforin and serine protease granzymes (Gzms) that induce cytolysis of the target cells. The hepatitis B virus (HBV) infection cause serious liver diseases worldwide. However, the clearance mechanism of HBV is not clear. HBV encodes four proteins：the envelope protein, the core protein, the reverse transcriptase, and the HBV X protein (HBx). The HBx a is 16.5-KDa regulator that is essential for virus replication². Previous studies indicated thatGzmH inhibits the viral replication by cleaving host or viral proteins³. In this study, the authors studied the role of GzmH in HBV clearance. They found that the granule exocytosis pathway is triggered by lymphokine-activated killer (LAK) cells, and in turn to inhibit HBV replication without cytolysis of target cells. GzmH blocks HBV replication by cleaving the HBx protein at the Met⁷⁹ residue. Inhibition of HBV replication was abolished by GzmH inhibitors. The HBx-deficient HBV is resistant to LAK cell- or GzmH-mediated viral clearance. Furthermore, HBV carrier mices transferred with the GzmH-overexpressing NK cells facilitate HBV eradication. Importantly, they found the cytotoxic lymphocytes of chronic HBV or hepatocellular carcinoma (HCC) patients express low GzmH. Taken together, GzmH is essential for HBV clearance. The expression level of GzmH may serve as a potential marker for diagnosis of HBV infection and HCC.

References

1.      Trapani, J. A., et al. 2002. Functional significance of the perforin/granzyme cell death pathway. Nat. Rev. Immunol. 2: 735–747.

2.      Xu, Z., et al. 2002. Enhancement of hepatitis B virus replication by its X protein in transgenic mice. J. Virol. 76: 2579–2584.

3.      Andrade, F., E. et al. 2007. Granzyme H destroys the function of critical adenoviral proteins required for viral DNA replication and granzyme B inhibition. EMBO J. 26: 2148–2157.