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