Metabolic dysfunction in T cells during hepatitis C virus infection

Abstract

T cell glucose metabolism is essential for the provision of energy to sustain and maintain T cell function, the so called, fuel for energy. In hepatitis C virus (HCV) infection, the immune response is a key determinant to outcome after primary infection, and with antiviral therapy for chronic HCV infection. The overall aim of this thesis was to examine T cell glucose metabolism in HCV infection and its association with T cell responses in chronic and primary HCV infection. To achieve this, key markers of glucose metabolism and T cell activation were studied in individuals with chronic HCV infection prior to receiving antiviral therapy and prior to primary infection. This is the first study to report that patients with chronic HCV infection demonstrate impaired glucose metabolism in both CD8 and CD4 T cells. Further, patients with chronic HCV infection who achieved viral clearance with PegIFN therapy, glucose metabolism as assessed by pAkt and glucose uptake, recovered to levels of healthy subjects. This data indicates dysfunctional T cell glucose metabolism may be a viral driven effect that may impact T cell function and viral clearance. Interestingly, low pAkt level was associated with reduced T cell activation markers (measured by CD25 and PD1) in both CD8 and CD4 T cells and their antigen-experienced subpopulations. Further, reduced pAkt level and T cell activation was associated with impaired production of effector antiviral cytokines in treatment non-responders. Lastly, non-responders had reduced frequency of terminally differentiated, effector and central memory T cells. The results from this study suggest that impaired T cell glucose metabolism, may affect T cell activation, function, effector phenotype differentiation and treatment outcome. Finally, the role of host related factors in potentially influencing the observed dysfunction in T cell glucose metabolism was further studied in individuals prior to primary HCV infection, and with known outcome from infection (spontaneous clearing versus chronic infection). The studies did not show any differences between the two groups before infection in terms of pAkt or glucose metabolism. Further, known SNPs within the Akt gene was not predictive of outcome of primary HCV infection. Thus, the xx results suggest that pre-existent host factors related to Akt does not predict acute HCV infection outcome. The data from this thesis indicate that HCV infection is associated with dysfunctional T cell glucose metabolism which may impact T cell activation, differentiation and the response to antiviral therapy. These studies are the first to report impaired T cell glucose metabolism during chronic HCV infection and improved our understanding of the relationship of HCV and T cell function.