title: Granzyme H of cytotoxic lymphocytes is required for clearance of the hepatitis B virus through cleavage of the hepatitis B virus X protein.
abstract: The granule exocytosis pathway of cytotoxic lymphocytes plays critical roles in eradication of intracellular viruses. However, how hepatitis B virus (HBV) is cleared has not been defined. To clarify immune mechanisms underlying inhibition of the HBV replication, the relationship between granzyme H (GzmH) and HBV clearance was investigated. In this study, we found that the granule exocytosis pathway can inhibit HBV replication without induction of cytolysis of the infected cells. GzmH is essential for HBV eradication. The HBx protein (HBx), required for the replication of HBV, is cleaved at Met(79) by GzmH. GzmH inhibitor can abolish GzmH- and lymphokine-activated killer cell-mediated HBx degradation and HBV clearance. An HBx-deficient HBV is resistant to GzmH- and lymphokine-activated killer cell-mediated viral clearance. Adoptive transfer of GzmH-overexpressing NK cells into HBV carrier mice facilitates in vivo HBV eradication. Importantly, low GzmH expression in cytotoxic lymphocytes of individuals is susceptible to HBV infection and hepatocellular carcinoma. These results indicate that GzmH might be detected as a potential parameter for diagnosis of HBV infection and hepatocellular carcinoma.
authors.affiliation: Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Haidong
authors.initials: H
authors.lastname: Tang
authors.forename: Chong
authors.initials: C
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Honglian
authors.initials: H
authors.lastname: Zhang
authors.forename: Zusen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D055612:Cytokine-Induced Killer Cells / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D053804:Granzymes / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D006801:Humans; D020014:K562 Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
chemical_list: D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C069434:GZMH protein, human; D053804:Granzymes