Endoplasmic Reticulum Aminopeptidase 1 Is Involved in Anti-viral Immune Response of Hepatitis B Virus by Trimming Hepatitis B Core Antigen to Generate 9-Mers Peptides

Abstract

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a processing enzyme of antigenic peptides presented to major histocompatibility complex (MHC) class I molecules. ERAP1-dependent trimming of epitope repertoire determines an efficacy of adoptive CD8+ T-cell responses in several viral diseases; however, its role in hepatitis B virus (HBV) infection remains unknown. Here, we show that the serum level of ERAP1 in patients with chronic hepatitis B (CHB) (n = 128) was significantly higher than that of healthy controls (n = 44) (8.78 ± 1.82 vs. 3.52 ± 1.61, p < 0.001). Furthermore, peripheral ERAP1 level is moderately correlated with HBV DNA level in patients with CHB (r = 0.731, p < 0.001). HBV-transfected HepG2.2.15 cells had substantially increased ERAP1 expression and secretion than the germline HepG2 cells (p < 0.001). The co-culture of ERAP1-specific inhibitor ERAP1-IN-1 pretreated HepG2.2.15 cells or ERAP1 knockdown HepG2.2.15 cells with CD8+ T cells led to 14–24% inhibition of the proliferation of CD8+ T cells. Finally, liquid chromatography tandem mass spectrometry (LC-MS/MS) test demonstrated that ERAP1-IN-1 blocks completely the production of a 9-mers peptide (30–38, LLDTASALY) derived from Hepatitis B core antigen (HBcAg). The predictive analysis by NetMHCpan-4.1 server showed that human leukocyte antigen (HLA)-C*04:01 is a strong binder for the 9-mers peptide in HepG2.2.15 cells. Taken together, our results demonstrated that ERAP1 trims HBcAg to produce 9-mers LLDTASALY peptides for binding onto HLA-C*04:01 in HepG2.2.15 cells, facilitating the potential activation of CD8+ T cells.

Epitope screening and vaccine molecule design of PRRSV GP3 and GP5 protein based on immunoinformatics

“…HTL candidate epitope prediction was used by the server NetMHCIIpanv4.0 EL (http://tools.iedb.org/mhcii/; Access: 2023.01). NetMHCIIpanv4.0 EL used artificial neural networks to predict peptide binding to any MHCII molecule of a known sequence 28 . The length of the predicted epitope was 15, and the screening criteria for the candidate epitope was set to the top 10% of the percentile.…”

“…NetMHCIIpanv4.0 EL used artificial neural networks to predict peptide binding to any MHCII molecule of a known sequence. 28 The length of the predicted epitope was 15, and the screening criteria for the candidate epitope was set to the top 10% of the percentile. Based on NetMHCIIpanv4.0 EL prediction, the server IFNepitope ( https://webs.iiitd.edu.in/raghava/ifnepitope/index.php ; Access: 2023.01) was used to predict the induction ability of candidate epitopes to IFN⁃γ.…”

Immune response and treatment targets of chronic hepatitis B virus infection: innate and adaptive immunity

“…IL-15 enhances NKG2Dmediated signaling by increasing the levels of NKG2D and expression of the intracellular adapter DAP10 through ERK phosphorylation. Activation of STAT1 can directly regulate the transcription of NKG2D, enhance the killing function of NK cells, and inhibit their apoptosis, thereby enhancing the immune response (Huang et al, 2022b). These targets modulate NK cells dysfunction in various ways.…”

“…Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims HBcAg-specific peptides and binds to HLA-C∗04:01. ERAP1 promotes CD8 + T cell-specific antiviral immune responses by presenting antigen peptides via major histocompatibility complex I molecules ( Liu et al., 2022b ). Hepatocytes are the natural targets of HBV, which leads to the activation and proliferation of CD8 + T cells; however, these cells do not differentiate into effector cells.…”

“…IL-21 promotes the expression of the basic leucine transcription factor (BATF) involved in initiating or maintaining HBV-specific CD8 + cell effector function by promoting the proliferation and production of IFN-γ, granzyme B, and CD107a and decreasing PD-1 and TIM-3 production ( Tang et al., 2019 ). IL-2 promotes the proliferation of CD8 + T cells by activating the mTOR pathway to restore dysfunctional CD8 + T cells caused by hepatocyte priming ( Liu et al., 2022b ).…”