Hepatic intrinsic immunity, referring to a set of cellular-based antiviral defense
mechanisms, is a front-line defense against HBV attack. PRRs play a key role in the intrinsic immune response, and the activation of PRRs by agonists contributes to control HBV replication.[3] However, increasing studies have provided evidence that the HBV infection interferes with PRR-mediated antiviral signaling in hepatocytes.[4, 5] For example, hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) or HBV virions nearly completely abolished TLR-induced antiviral capacity when pretreated with hepatocytes. Interferon (IFN)-β production and subsequent induction of interferon-stimulated genes, BVD-523 as well as activation of IFN regulatory factor 3 (IRF-3), nuclear factor (NF)-κB, and extracellular signal-regulated kinase (ERK) 1/2, were suppressed by the HBV components.[5] Also, HBV polymerase can interfere with IRF-3 activation and inhibit TLR3-mediated IFN-β induction in hepatocytes.[4] The reduction of TLR2 and TLR4 expression on hepatocytes
from fresh liver biopsies was observed in untreated HBeAg-positive CHB patients, which is associated with a functional decrease in cytokine production.[6, 7] These studies indicate that HBV can target TLRs and downstream signaling and thus attenuate the anti-HBV intrinsic immune responses. Furthermore, the role of the intracellular RIG-I–melanoma differentiation-associated gene 5 (MDA-5) Epigenetics Compound Library price innate see more immune system has been focused in HBV infection. HBx protein and HBV polymerase suppress type I IFN production by disrupting the virus-induced signaling
adapter-associated complex and interferes with RIG-I signal pathway in human hepatocytes,[4, 8-10] suggesting that HBV can target the RLR signaling, thereby attenuating the innate antiviral responses. In addition, the intrinsic antiviral defenses can be counteracted by HBx by inhibiting proteasome activities.[11] HBV precore/core proteins downregulates the expression of myxovirus resistance protein A (MxA), an important intrinsic antiviral factor, through direct interaction with MxA promoter.[12] These observations provide more evidence that HBV evolves multiple strategies to evade TLR/RIG-I-mediated antiviral signaling pathways, leading to cell-intrinsic immunotolerance (Fig. 1). Natural killer (NK) cells are important innate immune cells in antiviral immunity. In chronic HBV patients, the function of NK cells is impaired, demonstrated by the decreased number, the declined activation, the hampered IFN-γ production, and the attenuated cytolysis ability. The phenotype of NK cells was found changed, characterized by elevated expression of inhibitory receptor (such as natural killer group 2A [NKG2A]) and downregulated expression of activating receptors (such as CD16, NKG2D, and NKp30).