The Role of PD-1 and SOCS-1 in regulating T cell responses in HCV infection

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DESCRIPTION (provided by applicant): The role of PD-1 and SOCS-1 in regulating T cell responses in HCV infection. The overall goal of this study is to determine the role of the negative modulators, programmed cell death-1 (PD-1) and suppressor of cytokine signaling-1 (SOCS-1), in regulation of T cell responses during chronic hepatitis C virus (HCV) infection. HCV is remarkable at disrupting human T cell function and establishing persistent infection, thus providing an excellent model to study the mechanisms of virus-mediated T cell dysfunction. Our recent studies, both in vitro and ex vivo, have shown that HCV core protein can inhibit T cell responses through its interaction with a complement receptor, gC1qR, on T lymphocytes. Interestingly, this HCV core/gC1qR-mediated T cell dysfunction is associated with induction of PD-1 and SOCS-1. Additionally, gC1qR and PD-1 are found over- expressed on the surface of T cells in individuals chronically infected with HCV, although whether PD- 1 is up-regulated on viral specific T cells and its relationship to SOCS-1 in regulating T cell receptor (TCR) signaling remains unknown. Based on these intriguing findings and novel studies showing that both PD-1 and SOCS-1 play pivotal roles in negative regulation of TCR signaling during T cell activation, we hypothesize that PD-1 and SOCS-1 are up-regulated during HCV infection and lead to disruption of TCR signaling. As an initial approach to test this hypothesis, we will quantitatively analyze the kinetic expression of PD-1 and SOCS-1 in viral specific as well as total CD3+/CD4+ or CD3+/CD8+ T cells from chronically HCV- infected patients (interferon responders and non-responders, before and after treatment), and compare their levels with those of healthy blood donors. To gain insight into the mechanism(s) by which PD-1 and SOCS-1 regulate T cell responses, we will examine their roles in TCR signaling in T cells from HCV-infected patients. We will moreover dissect the relationships between gC1qR, PD-1, and SOCS-1 in regulating T cell responses that are critical for viral clearance. The proposed studies would potentially provide a novel mechanism by which pathogens usurp the host machinery to facilitate persistence, as well as a rationale for designing therapeutics and/or vaccine strategies for chronic viral infections. Hepatitis C virus (HCV) is a global health problem characterized by a high incidence of chronic infection, but how this virus is able to evade the human immune system remains unclear. In this proposal, we will examine the role of two novel modulators of immune responses, Programmed Death-1 (PD-1) and Suppressor of Cytokine Singaling-1 (SOCS-1), in regulating T cell responses that are impaired in chronic HCV infection. This study may reveal essential mechanisms by which viruses escape human immune surveillance to establish persistent infection.