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.
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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

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Figure 6

The antagonist form of CXCL10 (3–77 aa) is predictive of failure to achieve an EVR.

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The antagonist form of CXCL10 (3–77 aa) is predictive of failure to achi...
A prospective cohort was initiated and blood sampled in P700 collection tubes at the time point prior to treatment initiation. Thirty-four patients were followed clinically and classified based on their having achieved a 2-log reduction of viral load at week 12 of treatment (referred to as EVRs) or not (referred to as NRs). Plasma separated from the P700 tubes was analyzed using the CXCL10 3-plex. Plasma concentrations of total, long (1–77 aa), and short (3–77 aa) forms of CXCL10 are shown. Each symbol represents an individual patient; the black horizontal bars indicate the median. Mann-Whitney, 2-tailed comparison test was performed between EVRs and NRs, and P values are reported.