Intracellular Inactivation of the Hepatitis B Virus by Cytotoxic T Lymphocytes

Abstract

It is widely believed that viral clearance is mediated principally by the destruction of infected cells by CTLs. In this report, we use a transgenic mouse model of HBV replication to demonstrate that this assumption may not be true for all viruses. We find that adoptively transferred virus-specific CTLs can abolish HBV gene expression and replication in the liver without killing the hepatocytes. This antiviral function is mediated by IFNγ and TNFα secreted by the CTL or by the antigen-nonspecific macrophages and T cells that they activate following antigen recognition. These cytokines activate two independent virocidal pathways: the first pathway eliminates HBV nucleocapsid particles and their cargo of replicating viral genomes, while the second pathway destabilizes the viral RNA. Intracellular viral inactivation mechanisms such as these could greatly amplify the protective effects of the immune response, while failure of such mechanisms could lead to viral persistence or to the death of the host.