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.