γ-H2AX+CD8+ T lymphocytes cannot respond to IFN-α, IL-2 or IL-6 in chronic hepatitis C virus infection

Abstract

Background & AimsAge is the dominant prognostic factor influencing the natural history of hepatitis C virus (HCV) infection and treatment response. Accelerated lymphocyte telomere shortening in HCV infection correlates with adverse clinical outcomes. Critical telomere shortening generates double-stranded DNA breaks (DSB) inducing the DNA damage response, leading to replicative senescence. The phenotype and function of CD8+ T lymphocytes and the in vitro response to IFN-α in relation to the DNA damage response were investigated in patients with chronic HCV infection.MethodsCD8+ T lymphocytes with DSB were identified by expression of γ-H2AX (Ser-139) in 134 HCV-exposed subjects and 27 controls. Telomere length was determined by flow-FISH; cytokine expression by intracellular cytokine staining; in vitro responses to IFN-α, IL-2 or IL-6 by phospho-STAT1 (Y701) or phospho-STAT5 (Y694) expression.ResultsThe proportion of circulating CD8 + γ-H2AX+ T lymphocytes rose with increasing fibrosis stage (p = 0.0023). CD8 + γ-H2AX+ T lymphocytes were enriched in liver compared to blood (p = 0.03). CD8 + γ-H2AX+ T lymphocytes demonstrated increased IFN-γ (p = 0.02) and reduced IL-2 expression (p = 0.02). CD8 + γ-H2AX+ T lymphocytes failed to phosphorylate STAT1 in response to IFN-α compared to unfractionated CD8+ T lymphocytes (p <0.0001). More widespread failure of Jak/Stat signalling in CD8 + γ-H2AX+ T lymphocytes was suggested by impaired phosphorylation of STAT1 with IL-6 (p = 0.002) and STAT5 with IL-2 (p = 0.0039) compared to unfractionated CD8+ T-lymphocytes.ConclusionsIn chronic HCV infection, CD8 + γ-H2AX+ T lymphocytes are highly differentiated with shortened telomeres, are more frequent within the liver, are associated with severe fibrosis and fail to activate Jak/Stat pathways in response to IFN-α, IL-2 or IL-6, perhaps explaining treatment failure in those with severe fibrosis.

HCV monoinfection and HIV/HCV coinfection enhance T-cell immune senescence in injecting drug users early during infection

“…1a in CD8 + T cells over a period of 17 years. Using CD27/CD57 expression for defining immature (CD27 + CD57 - ), mature (CD27 - CD57 - ) and mature differentiated (CD27 - CD57 + ) phenotypes [ 29 , 30 ] (Fig. 1b ), we were also able to show differences in telomere length between these subsets (Fig.…”

Senescence mirrors the extent of liver fibrosis in chronic hepatitis C virus infection

“…During liver disease progression, senescence can be induced by telomere shortening or telemore‐independent mechanisms as a consequence of DNA damage and increased cell cycle turnover . Senescence in human liver diseases has been so far mainly assessed by detection of p21 in liver tissues .…”

“…During liver disease progression, senescence can be induced by telomere shortening or telemore-independent mechanisms as a consequence of DNA damage and increased cell cycle turnover. 11,22,23 Senescence in human liver diseases has been so far mainly assessed by detection of p21 in liver tissues. [8][9][10][11][12][13] Although senescence appears as an almost universal feature of chronic liver diseases, it is unknown whether senescence limits or promotes disease progression.…”

Hepatitis C virus promotes hepatocellular carcinogenesis by targeting TIPE2, a new regulator of DNA damage response

“…In fact, core, NS3/4A, NS5A, and NS5B have been reported to enhance DNA damage or suppress damage repair [9–13]. Consistently, in HCC patients, accumulation of DNA damage has been detected in the peripheral blood lymphocytes [14] and abundant H2AX + T lymphocytes were found in the liver [15]. …”