Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV
Armanda Casrouge, … , Stanislas Pol, Matthew L. Albert
Armanda Casrouge, … , Stanislas Pol, Matthew L. Albert
Published December 22, 2010
Citation Information: J Clin Invest. 2011;121(1):308-317. https://doi.org/10.1172/JCI40594.
View: Text | PDF
Research Article

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-α2 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.

Authors

Armanda Casrouge, Jérémie Decalf, Mina Ahloulay, Cyril Lababidi, Hala Mansour, Anaïs Vallet-Pichard, Vincent Mallet, Estelle Mottez, James Mapes, Arnaud Fontanet, Stanislas Pol, Matthew L. Albert

×

Figure 4

Induction of agonist CXCL10 results in rapid efflux of CXCR3+ T cells from the circulation.

Options: View larger image (or click on image) Download as PowerPoint
Induction of agonist CXCL10 results in rapid efflux of CXCR3+ T cells fr...
For 5 patients initiating peg–IFN-α2/ribavirin therapy, we monitored the plasma concentration of CXCL10 and the frequency of CXCR3-expressing cells. Results for a representative patient are shown. (A) Plasma levels of total CXCL10 (blue line), long-form CXCL10 (1–77 aa) (red line), and short-form CXCL10 (3–77 aa) (green line) are shown. (B) CXCR3-expressing T cells are shown at the time point prior to therapy (pre-tx; time, 0 hours) and 6 hours following initiation of treatment. (C) Total CXCL10 is represented by a black line, permitting comparison with the percentage of circulating CXCR3, represented by the orange line. (D) The absolute cell counts are shown for CXCR3+ and CXCR3– T cells. Values shown indicate the percent decrease for the respective populations of cells.