Role of the innate immune defenses in viral infections

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

A functional cure of chronic HBV infection is defined as absence of HBV DNA and HBsAg in the blood. PegIFNalpha treatment can achieve this cure, albeit only in a minority (2-10%) of chronically HBV infected patients. PegIFNalpha has both antiviral and immunomodulatory effects. Here, we assessed to which extend immunomodulatory effects contribute to the clinical response to PegIFN alpha therapy. Using sequential blood samples and liver biopsies of patients with chronic HBV infection prior to, during, and after PEG-IFNalpha treatment, we find differential activation of NK cells at an early time point (6h) after PEG-IFNalpha injection. Activation of and TRAIL induction on blood and liver NK cells correlated with ALT concentrations and HBV DNA release. Combined with colocalization of cleaved caspase 8 and TRAIL-receptor-expressing cells in the liver, these findings suggest that lysis of HBV-containing hepatocytes occurred. During follow-up, patients with an early NK cell response in blood and liver experienced greater HBsAg decline than patients without such a response. NK cell activation was associated with induction of interferon-stimulated genes and determined by PEG-IFNalpha pharmacokinetics. Patients with delayed increase in PEG-IFNalpha concentrations had greater amounts of PEG-specific IgM immune complexes in the blood and more PEG and IgM detected in the liver than patients with rapid increase in PEG-IFNalpha concentration. These results indicate that the immunomodulatory functions of PEG-IFNalpha play a pivotal role in the response to treatment and that peripheral blood NK cells can be studied as a biomarker. The results further demonstrate that these functions are affected by PEG-IFNalpha pharmacokinetics. To validate the finding that differential NK cell responses in the HBV cohort are driven by PEG-IFN pharmacokinetics, we studied a cohort of 84 hepatitis C virus (HCV)-infected patients who had also received PEG-IFNalpha-based therapy. PEG-IFNalpha-based therapy was the most effective treatment of chronic hepatitis C for two decades and the first-phase virological response predicts the treatment outcome. The HCV cohort therefore provided the opportunity to assess the relationship between PEG-IFNalpha concentration and early virological responses. As in the HBV cohort, a wide range of PEG concentrations was observed in the blood of the patients with chronic HCV infection 6h after the first PEG-IFNalpha injection. The plasma PEG concentration at that time point correlated with the induction of TRAIL expression on NK cells and with the plasma concentration of CXCL10, an inflammatory cytokine that is induced by IFNalpha. In addition, the plasma PEG-IFN concentration correlated with the first-phase virological response (r=-0.3244, p=0.0029). This correlation was confirmed after stratification for the rs12979860 (CC) haplotype, which is an independent strong predictor for a treatment response (r=-0.4328, p=0.019). These results confirm the relevance of PEG-IFNalpha pharmacokinetics in a second cohort of hepatitis patients. Differential drug pharmacokinetics s due to accelerated clearance of antibody-complexed pegylated drugs by Kupffer cells may be important beyond the field of chronic viral hepatitis and extend to treatment of other chronic diseases and cancer.