Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B.

Background & Aims: A better understanding of the immunomodulatory effects of PegIFNa therapy could allow more rational optimisation of future therapeutic approaches in chronic HBV infection. In this study, we evaluated dynamic changes in the innate and adaptive arms of the immune system induced by PegIFNa. Methods: PBMC were obtained from a cohort of patients with eAg-negative CHB before, during and after PegIFNa treatment. The number, phenotype and function of global and virus-specific T cells and NK cells were analyzed by flow cytometry and serum cytokines by ELISA or CBA. Results: The absolute number of CD8 T cells was strikingly reduced on PegIFNa therapy (p <0.001), with a predominant loss of end-stage effectors, including CMV-specific CD8 T cells. There was no significant recovery of the exhausted HBV-specific CD8 T cell response. By contrast, PegIFNa was able to potently and cumulatively drive the proliferation and expansion in absolute numbers of CD56bright NK cell numbers (p <0.001), with induction of the pro-proliferative cytokine IL-15. Expanded CD56bright NK cells showed enhanced expression of activation markers and the activating receptor NKp46, accompanied by augmentation of TRAIL and IFN-c expression (p <0.001). Peak virological response (temporal within individual patients and crosssectional within the cohort) correlated with the degree of expansion of functional CD56bright NK cells. Conclusions: IFN-a mediates divergent effects on the innate and adaptive arms of the immune system in vivo. The efficacy of Peg- IFNa may be limited by its depleting effect on CD8 T cells; conversely, it can cumulatively drive proliferation, activation and antiviral potential of CD56bright NK cells.