Natural killer (NK) and hepatitis B virus (HBV)-specific T cells are functionally impaired in chronic hepatitis B (CHB). Understanding to what extent nucleos(t)ide analogue (NUC) therapy can improve T- and NK-cell responses is important in the perspective of immunomonitoring strategies for a safe and earlier NUC withdrawal and of novel combination therapies based on modulation of antiviral immunity. To gain further insights into T/NK-cell interplay, we studied NK-cell phenotype and function in hepatitis B e antigen-negative chronic HBV patients either untreated (25) or NUC treated (36 hepatitis B surface antigen [HBsAg]+ and 10 HBsAg-/hepatitis B surface antibody [anti-HBs]+). Interferon-gamma, interleukin-2, and tumor necrosis factor alpha (TNF-α) production by HBV-specific T cells was also analyzed in NUC-treated patients. NK cells from chronic naïve patients showed an "inflammatory" phenotype defined by increased expression of TNF-related apoptosis-inducing ligand (TRAIL), CD38, and Ki67 that significantly declined upon viremia suppression and alanine aminotransferase normalization induced by NUC therapy. Reversion to a quiescent NK-cell phenotype was associated with restoration of the HBV-specific T-cell function. T- and NK-cell responses showed an inverse correlation, with an opposite behavior in individual NUC-treated patients. NK-cell depletion as well as TRAIL and NKG2D pathway blockade induced a significant improvement of the HBV-specific T-cell function. Conclusions: NK cells can express regulatory activity on T cells in NUC-treated patients with prevalent inhibition of CD4 T cells, likely needed to limit persistent T-cell activation. NK-cell phenotype is modulated by NUC therapy and its reversion to quiescence mirrors efficient HBV-specific T-cell responses. Thus, changes of NK-cell phenotype may predict acquisition of antiviral control before anti-HBs seroconversion and represent the groundwork for future studies aimed at assessing whether NK phenotyping can be translated into the clinical practice to guide NUC suspension.
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