A weak T cell response is presumably the main cause for HBV persistence. HBV-specific T cells could be anergized or exhausted by negative signals delivered via PD-1, CTLA-4, and Tim-3. Tregs, IL-10, TGF- β, and arginase could also suppress HBV-specific T cell responses. NK cells may also contribute to viral persistence by depleting HBV-specific T cells. Finally, APCs that acquire secreted subviral particles and proteins may develop immunoregulatory functions.