Spontaneous recovery from HBV and HCV infections is associated with vigorous virus-specific T cell responses. Conversely, chronic HBV and HCV infections are associated with decreased proliferation and decreased antiviral effector function of virus-specific T cells. This is thought to result from chronic T cell receptor stimulation by persisting viral antigens. It induces inhibitory molecules such as PD-1, Tim-3 and CTLA-4, and promotes an exhausted T cell phenotype that is also observed in diseases such as HIV infection and cancer. In addition, chronic HBV and HCV infections also share an inflammation-driven enhancement of natural killer (NK) cell function towards increased cytotoxicity and decreased production of antiviral cytokines. Antiviral drugs that rapidly clear HCV infection and significantly reduce HBV viremia provide an excellent clinical model to examine whether the described changes in T cell and NK cell function are reversible. Interferon (IFN)-based treatment is not suitable to answer this question because IFN exerts not only antiviral, but also immune-modulatory function. IFN-based therapies exacerbate the functional dichotomy of NK cells towards increased cytotoxicity and reduced IFN production and suppress proliferation and effector function of T cells. A lasting recovery of antiviral T cell responses has not been observed. Project 1: Hepatitis C virus infection In the past year, we have published that effective removal of HCV by IFN-free regimens of direct acting antivirals rapidly normalizes intrahepatic inflammation and innate immune cell activation. Specifically, NK cell activation decreases within the first 24 hours, and NK cell function normalizes by week 8 of therapy. In contrast, we did not observe any recovery of the IFN production of HCV-specific T cells when ex vivo or recall Elispot assays with sets of overlapping HCV peptides or minimal optimal T cell epitopes were performed with blood samples from the same patients. Combined, these results suggest that successful IFN-free therapy normalizes phenotype and function of NK cells, and that it restores the proliferative capacity, but not necessarily the ex vivo effector function of HCV-specific T cells. Project 2: Hepatitis B and D virus infection Hepatitis delta virus (HDV) is a small RNA virus that depends on hepatitis B virus (HBV) surface antigen to envelope its genome. Superinfection of chronic hepatitis B with HDV severely enhances inflammatory liver injury and progression to liver cirrhosis. The reason for the enhanced disease pathogenesis remains unknown. The adaptive and innate cellular immune response to HDV is poorly characterized and the reason for the enhanced disease pathogenesis in HBV/HCV coinfected patients remains unknown. We have previously studied T cell responses against HDV in an IFN-gamma Elispot assays with overlapping HDV peptides, and demonstrated both CD4 and CD8 T cell responses in those rare patients, who resolve HDV infection. We are now studying additional patients and are mapping minimal optimal T cell epitopes and their MHC restriction. To allow a broader analysis of innate and adaptive immune responses we are also conducting transcriptome analysis of peripheral blood mononuclear cells of HBV/HDV coinfected patients in comparison to that of HBV monoinfected patients and healthy controls.
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