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Review
. 2018 Jan;26(1):33-42.
doi: 10.1016/j.tim.2017.07.006. Epub 2017 Aug 16.

Mechanisms of Hepatitis B Virus Persistence

Kuen-Nan Tsai  1 , Cheng-Fu Kuo  1 , Jing-Hsiung James Ou  2
Affiliations
Review

Mechanisms of Hepatitis B Virus Persistence

Kuen-Nan Tsai et al. Trends Microbiol. 2018 Jan.

Abstract

Hepatitis B virus (HBV) chronically infects 250 million people worldwide, resulting in nearly one million deaths annually. Studies in recent years have significantly improved our knowledge on the mechanisms of HBV persistence. HBV uses multiple pathways to harness host innate immunity to enhance its replication. It can also take advantage of the developing immune system and the not-yet-stabilized gut microbiota of young children to facilitate its persistence, and use maternal viral e antigen to educate immunity of the offspring to support its persistence after vertical transmission. The knowledge gained from these recent studies paves the way for the development of new therapies for the treatment of chronic HBV infection, which has so far been very challenging.

Keywords: HBV e antigen; age and maternal effects; chronic hepatitis B; interferon immune responses; vertical transmission.

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Figures

Figure 1
Figure 1. Suppression of host innate immune response by HBV
HBV DNA polymerase (Pol) binds to DDX3 to suppress the activation of IRF3 and, although HBV pgRNA activates RIG-I to induce type III IFN via MAVS, TBK1 and IRF3, the binding of HBx to MAVS disrupts the RIG-I signaling pathway. HBcAg can activate TLR2 in Kupffer cells to induce the expression of the anti-inflammatory cytokine IL-10, and HBeAg can suppress TLR2 and TLR4 signaling in PBMC to inhibit the expression of TNF-α. Intracellular HBeAg can also bind to the TIR motif of TLRs to suppress TLR signaling.
Figure 2
Figure 2. Key role of Kupffer cells in HBV clearance and persistence
Kupffer cells can be activated via TLR4 by LPS produced by stabilized gut microbiota in adults to promote HBV clearance. They also express CXCL13 in an age-dependent manner to facilitate B cell trafficking and lymphoid development to direct immune responses against HBV. If Kupffer cells are not trained by maternal HBeAg, they will undergo M1 polarization to promote HBV clearance after the exposure to HBV antigens. However, if they are trained by maternal HBeAg, they will undergo M2 polarization in the presence of HBeAg to suppress HBV-specific CD8+ T cells to support HBV persistence.
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