T-lymphocyte senescence and hepatitis C virus infection

Change log
Hoare, Matthew 

Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma. The degree of fibrosis progression and treatment-related outcomes are critically dependent on the age of the infected individual. Progressive ageing is associated with a decline in the efficacy of adaptive immune system function. T-lymphocytes from aged subjects demonstrate multiple phenotypic and functional changes, including telomere shortening. Short telomeres are associated with poor proliferative capacity, pro-inflammatory responses and increased mortality in clinical studies. This research aimed to study telomere length changes in T-lymphocytes in chronic HCV infection and its relationship to clinical endpoints. Further, the intracellular signalling changes in T-lymphocytes with short telomeres were studied in subjects with chronic HCV. Short CD4+ T-lymphocyte telomeres were associated with the presence of severe hepatic fibrosis independent of other known factors. Telomere length was associated with blood markers of hepatic damage and dysfunction as well as histological markers of inflammation and fibrosis. Further, on prospective follow-up, short CD4+ telomere length at enrolment predicted progression to clinical endpoints of hepatic decompensation, development of hepatocellular carcinoma and death. Short CD4+ telomere length predicted a failure to respond to anti-viral treatment for HCV infection. Unexpectedly, subjects with non-viraemic HCV had short CD8+ telomere length. Liver biopsy tissue from a cohort of subjects with non-viraemic HCV was studied and demonstrated significant inflammation or fibrosis in most.
To study the IFN-α signalling pathway in cells with short telomeres, I utilised the phospho-histone γ-H2AX, a downstream signal from short telomeres. CD8+ T-lymphocytes expressing γ-H2AX had the form and function of cells with end-stage differentiation. γ-H2AX+ cells had a pro-inflammatory cytokine secretion profile with high expression of IFN-γ and low IL-2. Further γ-H2AX+ cells were unable to respond to exogenous IFN-α by phosphorylating Stat1. This failure was attributable to a post-receptor defect. T-lymphocyte telomere length changes in HCV may underpin the effect of age on clinical and treatment-related outcome. Short telomeres are associated with intracellular signalling defects which may explain the failure to respond to anti-viral therapy.

Hepatitis, Telomere, Senescence, Interferon
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge
My salary costs for the duration of this project were supported by a Clinical Research Training Fellowship from the Wellcome Trust and a scholarship from the Raymond and Beverley Sackler Foundation. Consumable expenses were supported by the Wellcome Trust, the Cambridge Hepatology endowment fund, the Frank Litchfield charitable trust and an unrestricted consumables grant from Roche (UK) pharmaceuticals.