Role of Dendritic Cell–Specific ICAM-3-Grabbing Nonintegrin on Dendritic Cells in the Recognition of Hepatitis B Virus

Abstract

Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is an essential process for virus infection, such as HIV and hepatitis C, and plays a role in immune escape. However, the role of DC-SIGN in hepatitis B virus (HBV) infection is still unknown. The aim of this study was to investigate the role of DC-SIGN in mediating the maturation and activation of dendritic cells (DCs) when infected by HBV. Highly mannosylated HBV particles were obtained by treating HBV-producing HepG2.2.15 cells with the a-mannosidase I-inhibitor kifunensine. Highly mannosylated HBV or wild type HBV was added to infect the DCs of the DC-SIGN gene-silencing group and normal group, respectively. Then, the expression of CDla, CD80, CD83, CD86 and HLA-DR on DCs was detected by flow cytometry, the capacity of stimulating lymphocyte proliferation was tested by MTT assay, the level of IL-12p70 that was released by DCs was measured by enzyme-linked immunosorbent assay, and the expression of the proteins NF-κBp65 and p38 was detected by western blot. Both wild type and highly mannosylated HBV could promote DCs maturation and activation. However, the highly mannosylated HBV could promote DCs immune activation more strongly. The difference in the effect on DCs between the two types of HBV could be eliminated by DC-SIGN gene silencing. DC-SIGN can promote the maturation and activation of DCs when recognized HBV, but wild type HBV can escape recognition by DC-SIGN to a certain extent with the help of demannosylated modification, leading to defective DCs function and chronic HBV infection.

Hepatitis B virus upregulates host expression of α-1,2-mannosidasesviathe PPARα pathway

“…Moreover, in our previous studies, we found that demannosylation is beneficial to HBV to escape DC-SIGN recognition[10]. Therefore, the upregulation of host α-mannosidases by HBV, as observed in this study, appears to contribute to viral escape[10]. …”

“…On the other hand, while the α-mannosidase I inhibitor kifunensine did not affect the production or secretion of HBV virus particles, it did increase its recognition by DC-SIGN, resulting in activation of the immune response[8,9]. Moreover, in our previous studies, we found that demannosylation is beneficial to HBV to escape DC-SIGN recognition[10]. Therefore, the upregulation of host α-mannosidases by HBV, as observed in this study, appears to contribute to viral escape[10].…”

“…Indeed, it has been shown that DC-SIGN does not recognize wild-type HBV but does recognize a high-mannose type HBV produced by the application of a class I α-mannosidase inhibitor, kifunensine[8,9]. Moreover, in our previous studies, we found that the high-mannose type HBV could promote the maturation of DCs, increase IL-12 secretion, and effectively stimulate the proliferation of allogeneic lymphocytes, and that these effects were blocked by specific anti-DC-SIGN antibodies[10]. Therefore, demannosylation appears to be beneficial to HBV to escape DC-SIGN recognition and avoid the consequent immune elimination.…”

N-Glycosylation and N-Glycan Processing in HBV Biology and Pathogenesis

“…In contrast, production of virions with high-mannose oligosaccharides in the presence of kifunensine resulted in DC-SIGN recognition and binding. More recently, the functional consequence of HBV binding to DC-SIGN was assessed by monitoring the DC maturation and activation when exposed to wild-type and highly mannosylated particles [ 46 ]. The study indicated that a stronger, DC-SIGN dependent immune activation occurs when DCs are stimulated with HBV exposing high-mannose N-linked glycans on the enveloped proteins.…”