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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) ). Interferon-gamma, interleukin-2, and tumor necrosis factor alpha (TNF-a) production by HBV-specific T cells was also analyzed in NUC-treated patients. NK cells from chronic na€ ıve 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. (HEPATOLOGY 2015;62:1697-1709 T reatment of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection is mainly based on nucleos(t)ide analogues (NUCs) that can induce persistent suppression of HBV replication in most treated patients, but can be safely stopped only after hepatitis B surface antibody (anti-HBs) seroconversion

X M Large S (env) Core His6 Untreated viremic CHB patients Low Cytokine production High Treg population Treg cells HBV-specific CD8+ T cells Combined GS-4774 and TDF therapy Immune Restoration High Cytokine production Treg cells HBV-specific CD8+ T cells Low Treg population BACKGROUND & AIMS: One strategy to treat chronic hepatitis B virus (HBV) infection could be to increase the functions of virus-specific T cells. We performed a multicenter phase 2 study to evaluate the safety and efficacy of GS-4774, a yeast-based therapeutic vaccine engineered to express HBV antigens, given with tenofovir disoproxil fumarate (TDF) to untreated patients with chronic HBV infection. METHODS: We performed an open-label study at 34 sites in Canada, Italy, New Zealand, Romania, South Korea, and United States from July 2014 to August 2016. Adults who were positive for HB surface antigen (HBsAg) > 6 months and levels of HBV DNA !2000 IU/ mL who had not received antiviral treatment for HBV within 3 months of screening were randomly assigned (1:2:2:2) to groups given oral TDF 300 mg daily alone (n ¼ 27; controls) or with 2, 10, or 40 yeast units GS-4774 (n ¼ 168), administered subcutaneously every 4 weeks until week 20 for a total of 6 doses. Blood samples were collected and analyzed and patients received regular physical examinations. Efficacy was measured by decrease in HBsAg from baseline to week 24. Specific responses to HBV (production of interferon gamma [IFNG], tumor necrosis factor [TNF], interleukin 2 [IL2], and degranulation) were measured in T cells derived from 12 HBeAg-negative patients with genotype D infections, after overnight or 10 days of stimulation of peripheral blood mononuclear cells with peptides from the entire HBV proteome. T-regulatory cells were analyzed for frequency and phenotype. Data from studies of immune cells were compared with data on reductions in HBsAg, HBV DNA, and alanine aminotransferase in blood