Toll-like receptor tolerance in dendritic cells during Hepatitis C and HIV infections: Collapsing the bridge between innate and adaptive immunity

Host anti-viral immune responses are thought to play a critical role in mediating the spontaneous clearance of Hepatitis C infection and slow progression of HIV disease. However, in hosts with chronic Hepatitis C infection or progressive HIV disease, anti-viral responses are ineffective at clearing virus and immunopathogenesis contributes to disease progression. The work presented in this thesis evaluates immune cell phenotype and function during chronic Hepatitis C and HIV infections. Our studies focused on dendritic cells, which provide a bridge between the innate and adaptive immune response. We evaluated dendritic cell phenotype, responsiveness to TLR stimulation, and capacity to activate NK cells and naïve CD4 T cells. In addition, we evaluated HCV infected host CD4 T cell phenotype and naïve CD4 T cell activation capacity in response to TCR activating signals. Our results indicate reduced numbers of MDC likely contribute to impaired NK cell activation in the setting of HIV infection. In addition, we observed selective defects in MDC response to TLR stimulation and MDC dependent naïve CD4 T cell activation in HIV infected subjects. Finally, our evaluation of CD4 T cells in Hepatitis C infected subjects indicated that naïve CD4 T cells were reduced in number, exhibited an increased activation state, and had reduced response to TCR stimulation. Taken together the results discussed in this thesis suggest alterations in number, phenotype, and function of dendritic cells and naïve CD4 T cells exist during chronic HCV and HIV infections. We propose a model in which chronic immune activation induces selective TLR tolerance in dendritic cells during chronic HCV and HIV infections. The tolerant state of the dendritic cells likely alters DC-NK cell and DC-naïve CD4 T cell interactions, which disrupts immune cell homoeostasis and proper immune cell activation, and in essence collapses the bridge between innate and adaptive immunity.HCV and HIV infections. We propose a model in which chronic immune activation induces selective TLR tolerance in dendritic cells during chronic HCV and HIV infections. The tolerant state of the dendritic cells likely alters DC-NK cell and DC-naïve CD4 T cell interactions, which disrupts immune cell homoeostasis and proper immune cell activation, and in essence collapses the bridge between innate and adaptive immunity.