Upregulation of NKG2C⁺ Natural Killer Cells, TLR-2 Expression on Monocytes and Downregulation of Regulatory T-Cells Influence PEG-IFN Treatment Efficacy in Entecavir-Suppressed Patients with CHB

Abstract

Successful response to PEG-IFN-α correlates with an early significant restoration of impaired immune responses. Although antiviral treatment response can be achieved by both IFN and ETV, the underlying immunological features vary which may explain the generally observed difference in off-treatment durability of response between the two treatments, as well as effects on HBsAg.

CD56bright natural killer cells induce HBsAg reduction via cytolysis and cccDNA decay in long‐term entecavir‐treated patients switching to peginterferon alfa‐2a

“…Recently, NKG2C + NK cells promoting a memory‐like response to certain viruses have been elucidated . We previously reported that a successful response to PegIFNα was associated with significant restoration of impaired immune responses manifested by decreased proportions and diminished inhibitory function of Tregs, increased proportions of NKG2C + NK cells, and higher proportions of TLR2 + CD14 + monocytes . These data suggested that modulating the number or function of Tregs, NK cells and monocytes in interferon‐based treatment may facilitate higher HBsAg clearance or clinical cure of HBV chronic infection through restoration of a robust immune response during anti‐HBV treatment.…”

“…In the OSST study, switching to 48 weeks of PegIFNα treatment from ETV significantly increased HBeAg seroconversion rate and HBsAg loss in CHB patients who had a long‐term ETV treatment with sustained HBV DNA suppression . Moreover, PegIFNα responders showed a significantly higher increase in the NKG2C + NK cell proportions from baseline to week 12 . But the detailed immunomodulation role of NK cells in HBV clearance has not been studied.…”

HBsAg seroclearance or seroconversion induced by peg-interferon alpha and lamivudine or adefovir combination therapy in chronic hepatitis B treatment: a meta-analysis and systematic review

“…The numbers and functions of Tregs and DCs are restored to normal levels after NA treatment (26,27). Thirdly, natural killer cell characteristics in CHB patients are associated with HBsAg clearance (28). Combination treatment with PEG-IFNα and ADV significantly influences NK-cell function (29,30).…”

The impact of currently licensed therapies on viral and immune responses in chronic hepatitis B: Considerations for future novel therapeutics

“…47 This has been further demonstrated where Peg-IFNα add-on was employed in patients virally suppressed with ETV, resulting in a reduction in T-reg frequencies with an increase in NKG2C+ NK cells and TLR-2+ CD14 monocytes, which was associated with treatment response. 94 In the same cohort, the expansion of CD56 bright NK cells expressing activatory receptors NKp30 and NKp46 along with TRAIL and IFNγ correlated with HBsAg decline with potential cccDNA clearance through TRAILinduced cytolysis, demonstrating the importance of Peg-IFNα for immune modulation and HBV clearance. 95 Similarly, in patients primed with Peg-IFNα prior to viral suppression, the maintenance of expanded functional CD56 bright NK cells has been shown to correlate with treatment response.…”

“…Viral load reduction is able to maintain the immune stimulatory effects of Peg‐IFNα, when administered in combination or sequence, compared to Peg‐IFNα alone, which implies there may be beneficial outcomes with add‐on or combination therapies . This has been further demonstrated where Peg‐IFNα add‐on was employed in patients virally suppressed with ETV, resulting in a reduction in T‐reg frequencies with an increase in NKG2C+ NK cells and TLR‐2+ CD14 monocytes, which was associated with treatment response . In the same cohort, the expansion of CD56 bright NK cells expressing activatory receptors NKp30 and NKp46 along with TRAIL and IFNγ correlated with HBsAg decline with potential cccDNA clearance through TRAIL‐induced cytolysis, demonstrating the importance of Peg‐IFNα for immune modulation and HBV clearance .…”