Mechanism of telomere attrition and premature T cell aging during HCV infection

East Tennessee State University, Johnson City TN

Investigators

Linked publications & trials

Abstract

Chronic viral infections appear to drive premature T cell aging, as evidenced by accelerated shortening of telomeres. However, how telomeres are trimmed to drive T cell aging during viral infection remains unclear. The goal of this study is to elucidate the mechanisms by which chronic viral infection accelerates the telomere attrition that may cause premature T cell aging, so as to develop effective means to improve cellular functions in virally infected individuals. To this end, we will employ hepatitis C virus (HCV) infection as a model system because i) HCV has a high rate (70%-80%) of persistence in humans; ii) the recent success in developing direct-acting antivirals (DAA) has resulted in a high rate (>95%) of viral clearance, providing an excellent opportunity to study the role of viral infection in modulating the host immunity before and after treatment in humans; iii) there is no vaccine available for HCV thus far, in part due to the unclear virus-host interactions that induce T cell senescence and immune dysfunction; and iv) we have recently found that CD4 T cells derived from HCV patients exhibit enhanced DNA damage and telomere erosion that are associated with a profound apoptotic and aging phenotype. Mechanistically, we have recently demonstrated that telomeric DNA damage and repair machineries are impaired in CD4 T cells during HCV infection: while the human telomerase reverse transcriptase (hTERT, the catalytic unit of telomerase that prolongs telomeric DNA) remains intact; the telomeric repeat binding factor 2 (TRF2, a telomere shelterin protein that protects telomeres from DNA damage) and the ataxia-telangiectasia mutated (ATM, a kinase that repairs the DNA damage) are inhibited in HCV CD4 T cells. We thus hypothesize that either an increased nuclease-mediated telomere trimming by aberrant telomeric DNA damage and repair signaling and/or a compromised telomeric DNA elongation is involved in the telomere attrition during chronic HCV infection. We designed two specific aims and will employ a translational approach using CD4 T cells from HCV-infected subjects before and after DAA treatment, to test our hypothesis. In Aim 1, we will identify the role of TRF2 in the telomeric DNA damage and telomere attrition during HCV infection. In Aim 2, we will elucidate the mechanisms involved in compromising telomeric DNA elongation during HCV infection. This translational study is novel and clinically significant in that it will explore mechanisms fundamental to diminishing T cell responses, and will address important questions as to how telomeric DNA is damaged to accelerate T cell aging and whether interfering with the enzyme involved in disrupting telomere integrity can remodel T cell function during viral infection. Understanding such mechanisms is critical for developing approaches to improve immune responses in the setting of various chronic infectious diseases, including but not limited to HCV infection.