Exploring immune modulating strategies to restore antiviral effector functions of intrahepatic CD8 T cells

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Reconstitution of antiviral immunity by vaccination is an attractive option to specifically control chronic hepatitis B virus (HBV) infection. To characterize HBV-specific CD8 T cell responses in the presence of a liver that produces all HBV antigens, we established the 1.4HBV-Smut transgenic (tg) line that harbours a replicating HBV genome in the liver, produces HBV large/middle surface (S) and core/precore (C/E) antigens but secretes neither small S particles, nor HBV virions. DNA vaccines efficiently induce core- (but not S-) specific CD8 T cell responses that transiently suppress HBV replication in the liver of 1.4HBV-Smut tg mice. Intrahepatic, specific CD8 T cells in vaccinated 1.4HBV-Smut tg mice show reproducible changes in their phenotype and cytokine profile that coincide with their loss of antiviral activity (‘exhaustion’). The proposal aims to elucidate systemic and intrahepatic regulatory effects that set off ´exhaustion´ of specific CD8 T cells in vaccinated 1.4HBV-Smut tg mice. We will use 1.4HBV-Smut tg mice crossed to well-defined tg or KO lines (deficient for coinhibitory molecules, regulator cells or cytokines) and vaccinated with HBcAg- or HBsAg-encoding vaccines. We will combine specific vaccination with antiviral drug (Tenofovir®) treatment and/or immune modulating protocols in an attempt to maintain an antiviral phenotype in the specific, intrahepatic T cells. We are in particular interested in: (i) the characterization of the kinetics of primary and boosted CD8 T cell responses in wt versus tg animals; (ii) changes in phenotype and cytokine secretion of CD8 T cells and hepatocytes; and (iii) epitope specificities of CD8 T cells. To selectively analyze intrahepatic effector CD8 T cell responses, we will use adoptive transfer experiments (CD8 T cells from vaccinated wt or KO mice transferred into wt or KO 1.4HBV-Smut tg mice). These studies may help to rationally design specific immune intervention protocols that attenuate the functional ‘exhaustion’ of CD8 T cells in chronic infection with hepatotropic viruses.