Regulation of Human Monocytes by HCV

Hepatitis C virus (HCV) infection is highly efficient in the establishment of persistent infection, leading to the development of chronic liver disease and hepatocellular carcinoma. Persistent HCV infection is associated with impaired T cell responses. Extracellular HCV core is a viral factor known to cause HCVinduced T cell impairment via its suppressive effect on innate immune cells. This dissertation will investigate the molecular mechanisms for HCV core mediated regulation of innate immune cells, and the capacity of HCV core to alter the function of these important immune cells. The activation of STAT3 has been reported to inhibit the activation of antigen presenting cells (APCs). In chapter 2 of this dissertation, we report the activation of STAT3 in human APCs following treatment with extracellular HCV core. Additionally, we show that treatment with an agonistic monoclonal antibody to HCV core ligand, gC1qR, also activates STAT3. Importantly, the production of multifunctional cytokine IL-6 is essential for HCV core-induced STAT3 activation. Given the role of STAT3 in limiting APC activity, the results presented here suggest that HCV core-induced STAT3 activation plays a critical role in the alteration of inflammatory responses by APCs, leading to impaired anti-viral T cell responses during HCV infection. Myeloid derived suppressor cells (MDSCs) play a pivotal role in suppressing T cell responses. In chapter 3 of this dissertation, we examine the accumulation of ii MDSCs in human PBMCs following HCV infection. We found that CD33 + cells co-cultured with HCV-infected hepatocytes, or with HCV core, suppress T cell activation through the production of reactive oxygen species (ROS). Importantly, CD33 + cells from chronic HCV patients mirror HCV core treated CD33 + cells. These results suggest that HCV promotes the accumulation of CD33 + MDSCs, resulting in ROS-mediated suppression of T cell responsiveness. The results presented in this dissertation show that HCV modulates innate immune cells through the release of extracellular core protein. Specifically, we show that HCV core protein activates immunosuppressive transcription factor, STAT3, and leads to the generation of MDSCs. Thus, HCV core may facilitate HCV persistent infection by modulating the innate immune cell population and generating an immunosuppressive innate immune cell. iii Dedication This thesis is dedicated to my wife, Trisha Marden Tacke, and to my parents Sam and Jayne Tacke.

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