Hepatitis B virus upregulates host expression of a-1,2-mannosidases via the PPARa pathway

Hu, Song; Jiang, Li-Bin; Zou, Xiao-Jing; Yi, Wei; Tian, De-Ying

Hepatitis B virus (HBV) infection is the most common chronic viral infection in the world. An estimated 2 billion people are infected, and more than 350 million are chronic carriers of the virus [1] . Due to an insufficient immune response, some individuals with HBV infection can develop chronic hepatitis, which can eventually result in liver cirrhosis and hepatocellular carcinoma (HCC). While the underlying mechanisms for HBV-induced chronic hepatitis remain unclear, several studies indicate that dendritic cell (DC) function is impaired in patients with chronic hepatitis B [2, 3] . DCs are potent antigen-presenting cells (APCs) that can present antigen to T cells and activate naive T cells. Multiple receptor molecules on the surface of DCs, including Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), participate in the recognition and uptake of pathogens, and can regulate the expression of co-stimulatory molecules [4] . In particular, DCspecific ICAM-3 grabbing non-integrin (DC-SIGN) is an important CLR that is mainly expressed on the surface of mature and immature DCs [5] . DC-SIGN plays an important role in the recognition of pathogen-associated molecular patterns (PAMPs) [5] . Moreover, previous studies have shown that DC-SIGN is involved in the immune escape of multiple pathogenic microorganisms, including HIV-1, Ebola virus, hepatitis C virus (HCV), Dengue fever virus, cytomegalovirus (CMV), SARS-coronavirus, mycobacterium tuberculosis, Helicobacter pylori, fungus, and some parasites [6, 7] . Unfortunately, the mechanisms behind immune escape mediated by DC-SIGN remain unclear. It may be that DC-SIGN directly recognizes mannose oligosaccharides found on the viral envelope of HBV. Through modifications to these mannose oligosaccharides on its viral envelope, HBV could potential evade the host immune system. 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 â… Î±-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. Demannosylation of glycoproteins occurs through a family of mannosidases that trim mannan in the N-oligosaccharide. Human Class â… Î±-mannosidases include the ER α-1, 2-mannosidase I (MAN1B1), and three Golgi α-1,2-mannosidases, namely α-mannosidase IA (MAN1A1), α-mannosidase IB (MAN1A2), and α-mannosidase IC (MAN1C1). Generally, MAN1B1 firstly trims α-1,2-mannose from Man9GlcNAc2-Asn, and then MAN1A1, MAN1A2, and MAN1C1 trim the residual α-1,2-mannose, to generate Man5GlcNAc2-Asn. These processes are dependent on the varying levels of the mannosidase subtypes in different cell types [11] . There are glycosylation sites on the surface of HBV envelope proteins, which could be glycosylated by the host [12] . Therefore, it is not surprising that HBV infection has previously been shown to upregulate the expression of ER degradation-enhancing α-mannosidases (EDEMs) in order to increase demannosylation [13] . However, few studies have investigated the effects of HBV on the expression of class â… Î±-mannosidases.