Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV

Abstract

Chronic infection with hepatitis C virus (HCV) is a major public health problem, with nearly 170 million infected individuals worldwide. Current treatment for chronic infection is a combination of pegylated IFN-α 2 and ribavirin (RBV); however, this treatment is effective in fewer than 50% of patients infected with HCV genotype 1 or 4. Recent studies identified the chemokine CXCL10 (also known as IP-10) as an important negative prognostic biomarker. Given that CXCL10 mediates chemoattraction of activated lymphocytes, it is counterintuitive that this chemokine correlates with therapeutic nonresponsiveness. Herein, we offer new insight into this paradox and provide evidence that CXCL10 in the plasma of patients chronically infected with HCV exists in an antagonist form, due to in situ amino-terminal truncation of the protein. We further demonstrated that dipeptidyl peptidase IV (DPP4; also known as CD26), possibly in combination with other proteases, mediates the generation of the antagonist form(s) of CXCL10. These data offer what we believe to be the first evidence for CXCL10 antagonism in human disease and identify a possible factor contributing to the inability of patients to clear HCV.

Linagliptin-Mediated DPP-4 Inhibition Ameliorates Kidney Fibrosis in Streptozotocin-Induced Diabetic Mice by Inhibiting Endothelial-to-Mesenchymal Transition in a Therapeutic Regimen

“…Also, our data indicate that TGF-b2/DPP-4/miR29s display cross-talk mechanisms in the onset of kidney fibrosis, and linagliptin-mediated inhibition of DPP-4 would diminish profibrotic signaling cross-talk in the kidney. Among human fibrotic diseases, patients with hepatitis C viral infections, the condition associated with microRNA 29 suppression, also exhibit high DPP-4 activity; such DPP-4 activity could be a potential target for combating such liver diseases (37). Further study is required to determine whether DPP-4 activity is greater in type 1 or type 2 diabetic kidney diseases, or in other fibrotic chronic and acute diseases, including kidney disease, and their association with microRNA 29s levels in humans.…”

Chemokine antagonism in chronic hepatitis C virus infection

“…In these chronically infected individuals, HCV-specific T cells are ineffective at eradicating virus, yet are potent mediators of hepatocellular injury. Evidence presented in this issue of the JCI by Casrouge et al (4) suggests that chemokine antagonism may contribute to this inability to clear HCV infection. Their data (4) also provide an explanation as to why high levels of the chemokine CXCL10 in the plasma or serum of an HCV-infected patient portend a poor response to peg-IFN-α and ribavirin (5)(6)(7)(8).…”

“…FA is caused by mutations in one of fourteen or more genes (the so-called FA genes), whose products cooperate to ensure the repair of interstrand crosslinks that form during DNA replication (i.e., during the S phase of the cell cycle) (2). Failure to repair these lesions efficiently leads to the activation of S and G 2 cell cycle checkpoints that trigger cell cycle arrest (3,4). Failure of cells, particularly HSCs and blood cell precursors, to progress through the cell cycle has been thought to contribute to the BMF experienced by patients with FA (5).…”

Emerging concepts in immunity to hepatitis C virus infection

“…The favorable IFNL3 variant is associated with lower ISG expression in pretreatment liver biopsies (39), and exogenous IFN-α induces a rapid antiviral state (40). Interestingly, serum levels of IFN-γ-induced protein 10 (IP-10 or CXCL10), a well-characterized marker of HCV (41) that may antagonize T cell recruitment in chronic infection (42), enhance the predictive value of the IFNL3 genotype in patients receiving dual therapy (43). In addition, the dinucleotide ss469415590 variant of IFNL4 (44), a newly identified gene upstream of IFNL3, provides an even greater prediction of impaired viral kinetics among African-Americans than rs12979860 variants of IFNL3 (44).…”