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The paradoxical role of type I interferons in Hepatitis C disease pathogenesis and treatment

Final Report Summary - HCV_IMMUNOLOGY (The paradoxical role of type I interferons in Hepatitis C disease pathogenesis and treatment)

More than 150 million people worldwide suffer from a hepatitis C virus (HCV) infection, which if left untreated, results in a greatly increased risk of liver failure and hepatocellular carcinoma (HCC). One of the greatest difficulties in diagnosing HCV is that the acute stage is often asymptomatic. Spontaneous viral clearance occurs in as many as 45% of infected adults but the majority of cases progress to chronic infection. Eight to twenty percent of chronic infections will develop cirrhosis within 20 years and many are faced with a lifetime risk of HCC. The severe consequences resulting from disease progression make it critical that the appropriate therapeutic action is taken to prevent unnecessary liver damage.

At the time of project submission, the standard of care for patients with HCV was treatment with pegylated-interferon and ribavirin. This therapy was only successful in producing a sustained virological response for a subset of the infected individuals and there are a number of independent factors may be responsible for the low success rate of approximately 50%. As interferon therapy had severe side-effects, it was beneficial to predetermine those patients who will respond to treatment. And it is still, as many HCV patients in developing / emerging countries do not have access to the latest treatments.

In the recent years, IP-10 has become a particularly interesting biomarker in the study of HCV. In patients with chronic HCV infections, intrahepatic IP-10 mRNA levels correlate with plasma concentrations of IP-10, indicating that HCV-infected hepatocytes are the primary source of the plasma biomarker. Furthermore, it was determined that the pre-treatment plasma levels of IP-10 were greatest in those patients who would become “non-responders” to pegylated interferon (IFN) antiviral therapy. The utility of IP-10 to predict treatment outcome was confirmed in our recent study, which found IP-10 levels valuable in predicting a sustained viral response to the standard of care in HCV infected individuals with 81% specificity and 95% sensitivity.

It was considered counterintuitive that a chemokine responsible for recruiting activated lymphocytes to the liver, is a negative prognostic marker for response to therapy. One explanation is that alternative forms of the IP-10 protein are interfering with its normal function. We have demonstrated that the enzyme dipeptidyl peptidase IV (DPP4) cleaves IP-10, resulting in truncated forms of the proteins that exhibit lower biological activity. We proposed that DPP4 cleavage of IP-10 leads to an increased presence of the short form IP-10 protein, which could account for the failure of treatment in certain individuals. Indeed, the researchers found that the increase in the levels of total IP-10 in non-responding HCV patients was due to an elevation of the antagonist (short).

It appears that the short IP-10 interferes with the chemokine gradient that is required for patients’ successful response to therapy. In this example, treatment decisions could be improved dramatically by measuring both forms of the IP-10 protein to make predictions about patient outcome; and current efforts aim to extend these findings to questions of cell migration in the context of other chronic infections and cancer.