Hepatitis C virus (HCV) establishes chronic infection in the liver of nearly 80% of those infected and in addition to causing hepatitis, may cause liver cirrhosis and hepatocellular carcinoma. These detrimental long-term sequelae of persistent HCV infection now comprise the leading indication for liver transplantation in the United States. Defining the elements of the immune response that fail or are insufficient to mediate HCV clearance or resolution in the majority of those infected is critical for advancing our understanding of how to therapeutically intervene in HCV disease pathogenesis. It is known in murine models that a subset of liver dendritic cells, pDCs, express the co-inhibitory molecule B7-H1 to mediate PD-1 dependent T cell dysfunction and that another subset, the mDCs, are capable of inhibiting T cell proliferation and inducing T cell apoptosis. Therefore we hypothesized that defects in DC function might contribute to the establishment of chronic HCV infection. In looking at DC populations in HCV-infected liver we observed: (i) a marked absence of a novel population of myeloid DC progenitors, (ii) an influx of mature DCs compared to uninfected liver and (iii) an activated DC population expressing high levels of T cell co-stimulatory and co-inhibitory molecules. Based on these data we now hypothesize that the chronic HCV liver microenvironment promotes the differentiation of myeloid liver DCs, and that these DCs skew HCV-specific T cell responses toward the induction of tolerance through B7-mediated inhibition and aberrant cytokine secretion. We now propose to study the effects of HCV infection on liver DC recruitment and activation and to test the capacity of liver DC subsets from chronically infected patients to process and present HCV-derived antigens to CD4+ and CD8+ T cells. These studies will identify potential defects in the functional DC response to HCV-infection, and will reveal potential targets for therapeutic intervention.
Hepatitis C virus (HCV) infection is a major global health problem;there are currently 2.5 million Americans chronically infected with HCV and this number increases to a staggering 170 million worldwide. A significant number of these individuals will go on to develop severe complications including liver cirrhosis and hepatocellular carcinoma. We are seeking to understand the mechanisms by which host immune response fails in the majority of those infected and reveal potential targets for therapeutic intervention.
| Thapa, Manoj; Chinnadurai, Raghavan; Velazquez, Victoria M et al. (2015) Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity. Hepatology 61:2067-79 |
| Velazquez, Victoria M; Uebelhoer, Luke S; Thapa, Manoj et al. (2015) Systems biological analyses reveal the hepatitis C virus (HCV)-specific regulation of hematopoietic development. Hepatology 61:843-56 |
| Mimche, Patrice N; Brady, Lauren M; Bray, Christian F et al. (2015) The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice. Hepatology 62:900-14 |
| Khan, Abdul Ghafoor; Whidby, Jillian; Miller, Matthew T et al. (2014) Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2. Nature 509:381-4 |
| Dunham, Richard M; Thapa, Manoj; Velazquez, Victoria M et al. (2013) Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid. J Immunol 190:2009-16 |
| Fuller, Michael J; Callendret, Benoit; Zhu, Baogong et al. (2013) Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1). Proc Natl Acad Sci U S A 110:15001-6 |
| Shin, Gyehwa; Yost, Samantha A; Miller, Matthew T et al. (2012) Structural and functional insights into alphavirus polyprotein processing and pathogenesis. Proc Natl Acad Sci U S A 109:16534-9 |
| Velazquez, Victoria M; Hon, Huiming; Ibegbu, Chris et al. (2012) Hepatic enrichment and activation of myeloid dendritic cells during chronic hepatitis C virus infection. Hepatology 56:2071-81 |
| Chinnadurai, R; Velazquez, V; Grakoui, A (2012) Hepatic transplant and HCV: a new playground for an old virus. Am J Transplant 12:298-305 |
| Sharma, Nishi R; Mateu, Guaniri; Dreux, Marlene et al. (2011) Hepatitis C virus is primed by CD81 protein for low pH-dependent fusion. J Biol Chem 286:30361-76 |
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