NK cells are important antiviral effectors, highly enriched in the liver, with the potential to regulate immunopathogenesis in persistent viral infections. Here we examined whether changes in the NK pool are induced when patients with eAg-positive CHB are ‘primed’ with PegIFNα and importantly, whether these changes are sustained or further modulated long-term after switching to nucleos(t)ides (sequential NUC therapy), an approach currently tested in the clinic. Longitudinal sampling of a prospectively recruited cohort of patients with eAg+CHB showed that the cumulative expansion of CD56bright NK cells driven by 48-weeks of PegIFNα was maintained at higher than baseline levels throughout the subsequent 9 months of sequential NUCs. Unexpectedly, PegIFNα-expanded NK cells showed further augmentation in their expression of the activating NK cell receptors NKp30 and NKp46 during sequential NUCs. The expansion in proliferating, functional NK cells was more pronounced following sequential NUCs than in comparison cohorts of patients treated with de novo NUCs or PegIFNα only. Reduction in circulating HBsAg concentrations, a key goal in the path towards functional cure of CHB, was only achieved in those patients with enhancement of NK cell IFNγ and cytotoxicity but decrease in their expression of the death ligand TRAIL. In summary, we conclude that PegIFNα priming can expand a population of functional NK cells with an altered responsiveness to subsequent antiviral suppression by NUCs. Patients on sequential NUCs with a distinct NK cell profile show a decline in HBsAg, providing mechanistic insights for the further optimisation of treatment strategies to achieve sustained responses in CHB.
Author Summary
Current therapies for CHB are limited in achieving HBsAg decline and loss leading to a cure. Although PegIFNα may be used, the majority of patients progress to NUC therapy due to treatment failure. PegIFNα and NUCs used in isolation act differentially on the immune response; PegIFNα induces NK cell activation and NUC therapy may partially restore T cell function. Data, however, are limited on the immune effects when these therapies are used in sequence or in combination. Here, we analysed the immune effects of PegIFNα followed by sequential NUC therapy and show this treatment strategy maintains the cumulative expansion of antiviral CD56bright NK cells, following PegIFNα-priming. HBsAg reduction was greater in patients treated with sequential NUCs when compared with de novo NUCs, highlighting the potential benefit of PegIFNα-priming. Such sustained boosting of NK cells on sequential NUCs following PegIFNα-priming has not previously been described, raising the potential of ‘long-lived’ NK cell populations in keeping with their emerging adaptive features. These findings provide a mechanistic and immunological rationale to explore this treatment strategy for CHB whilst awaiting the emergence of new therapies in the field.