This prospective study investigated viral and host markers after stopping long-term therapy with nucleos(t)ide analogues in noncirrhotic patients with hepatitis B e antigen–negative chronic hepatitis B. After stopping therapy, 13 of 15 patients experienced a virological relapse. Rebound of hepatitis B virus DNA and hepatitis B core-related antigen was associated with induction of plasma tumor necrosis factor, interleukin (IL) 10 , IL-12p70, CXCL10 and subsequent decline in hepatitis B surface antigen (HBsAg), with 20% HBsAg loss after long-term follow-up. The peak levels of hepatitis B virus DNA and hepatitis B core-related antigen after cessation of therapy were positively correlated with the level of HBsAg decline at week 48. Thus, stopping or interrupting NA treatment should be further investigated as a strategy to accelerate HBsAg loss.

Cytolytic CD8⁺ T cells are critical for the control of acute Friend virus (FV) infection yet they fail to completely eliminate the virus during chronic infection because they are functionally impaired by regulatory T cells (Treg). We performed a kinetic analysis of T cell responses during FV infection to determine when dysfunction of CD8⁺ T cells and suppressive activity of CD4⁺ regulatory T cells develops. At 1 week post infection, virus‐specific CD8⁺ T cells with effector phenotype and cytolytic potential expanded. Peak expansion was found at 12 days post infection, correlating with peak viral loads. After 2 weeks when viral loads dropped, numbers of activated CD8⁺ T cells started to decline. However, a population of virus‐specific CD8⁺ T cells with effector phenotype was still detectable subsequently, but these cells had lost their ability to produce granzymes and to degranulate cytotoxic molecules. Contemporaneous with the development of CD8⁺ T cell dysfunction, different CD4⁺ T cell populations expressing cell surface markers for Treg and the Treg‐associated transcription factor Foxp3 expanded. Transfer as well as depletion experiments indicated that regulatory CD4⁺ cells developed during the second week of FV infection and subsequently suppressed CD8⁺ T cell functions, which was associated with impaired virus clearance.

Hepatitis B virus (HBV)-specific CD8⁺ T cells play a dominant role during acute-resolving HBV infection but are functionally impaired during chronic HBV infection in humans. These functional deficits have been linked with metabolic and phenotypic heterogeneity, but it has remained unclear to what extent different subsets of HBV-specific CD8⁺ T cells still suppress viral replication. We addressed this issue by deep profiling, functional testing and perturbation of HBV-specific CD8⁺ T cells during different phases of chronic HBV infection. Our data revealed a mechanism of effector CD8⁺ T cell attenuation that emerges alongside classical CD8⁺ T cell exhaustion. Attenuated HBV-specific CD8⁺ T cells were characterized by cytotoxic properties and a dampened effector differentiation program, determined by antigen recognition and TGFβ signaling, and were associated with viral control during chronic HBV infection. These observations identify a distinct subset of CD8⁺ T cells linked with immune efficacy in the context of a chronic human viral infection with immunotherapeutic potential.