Pathogenesis Of HBV Infection Research Articles

MTOR Signaling: Roles in Hepatitis B Virus Infection and Hepatocellular Carcinoma.

Currently, chronic hepatitis B virus infection is still one of the most serious public health problems in the world. Though current strategies are effective in controlling infection and slowing down the disease process, it remains a big challenge to achieve a functional cure for chronic hepatitis B in a majority of patients due to the inability to clear the cccDNA pool. The mammalian target of rapamycin (mTOR) integrates nutrition, energy, growth factors, and other extracellular signals, participating in gene transcription, protein translation, ribosome synthesis, and other biological processes. Additionally, mTOR plays an extremely important role in cell growth, apoptosis, autophagy, and metabolism. More and more evidence show that HBV infection can activate the mTOR pathway, suggesting that HBV uses or hijacks the mTOR pathway to facilitate its own replication. Therefore, mTOR signaling pathway may be a key target for controlling HBV infection. However, the role of the central cytokine mTOR in the pathogenesis of HBV infection has not yet been systematically addressed. Notably, mTOR is commonly activated in hepatocellular carcinoma, which can progress from chronic hepatitis B. This review systematically summarizes the role of mTOR in the life cycle of HBV and its impact on the clinical progression of HBV infection.

Correlation between plasma levels of sPD-1 and sPD-L1 with hepatic inflammation in chronic HBV infected patients

Objective: The immunosuppressive PD-1/PD-L1 (programmed cell death-1/ programmed cell death ligand-1) signaling pathway is considered to play an important role in the pathogenesis of HBV infection. We conducted a prospective cohort study to assess the relationship between circulating sPD-1 and sPD-L1 (soluble forms) levels in HBV infection and live disease outcome and progression. Subject and method: Plasma sPD-1 and sPD-L1 levels were quantified using commercial ELISA kits in a prospective cohort including asymptomatic carrier (ASY, n = 30), chronic hepatitis (CHB, n = 79), hepatocellular carcinoma (HCC, n = 47) and 73 healthy individuals as control group (HC). Result: The plasma sPD-1 and sPD-L1 levels were significantly higher in HBV infected patients or in each patient groups (ASY, CHB, HCC) compared to the controls (p<0.0001). Among HBV-infected patients, plasma sPD-1 and sPD-L1 levels were higher in the CHB followed by the HCC and ASY group. The plasma levels of sPD-1 and sPD-L1 were positively correlated with hepatic inflammation markers such as AST, ALT and GGT in HBV- infected patients. Conclusion: We could show that HBV infection can induce the expression of PD-1 and PD-L1 and significantly increased levels of plasma sPD-1 and sPD-L1 are correlated with the hepatic inflammation in chronic HBV-infected patients.

The potential role of HLA-G in the pathogenesis of HBV infection: Immunosuppressive or immunoprotective?

The non-classical human leukocyte antigens (HLA)-G could be generally considered as a potent tolerogenic molecule, which modulates immune responses. HLA-G due to the immunosuppressive properties may play an important role in the pathogenesis of infections related to the liver. HLA-G may display two distinct activities in the pathological conditions so that it could be protective in the autoimmune and inflammatory diseases or could be suppressive of the immune system in the infections or cancers. HLA-G might be used as a novel therapeutic target for liver diseases in the future. Indeed, new therapeutic agents targeting HLA-G expression or antibodies which block HLA-G activity are being developed and tested. However, further consideration of the HLA-G function in liver disease is required. This review aims to summarize the role of HLA-G in the liver of patients with HBV infection.

Association between Human Leukocyte Antigen-DQ Polymorphisms and Treatment Response in Chronic Hepatitis B Egyptian Population: A Prospective Study

Background & Aims: Several studies, in different populations, have focused on the role of HLA-DQ gene polymorphism in the pathogenesis of HBV infection. However, these findings are still controversial. This study aimed to determine HLA-DQ polymorphism in Chronic HBV patients and its impact on the response to antiviral therapy. Methods: This study was carried out on a total number of 188 participants, they were subdivided as follows: Group I (patients’ group): included 97 patients with chronic hepatitis B viral infection that was further subdivided according to response to treatment into responder and non-responder subgroups, Group II (Control group): included 91 normal healthy subjects who were matched to the patient group by sex and age. PCR (Polymerase Chain Reaction) testing, for HBV-DNA, was done for all participants enrolled in the study to measure the viral virus load before and after treatment. HLA- DQ polymorphism allelic discrimination assay was assayed using the Real-time equipment. Results: In a general analysis for the SNP rs7453920, the overall genotypes frequencies were 37% for A/A, 60.6% for A/G, and 37% for G/G. The G alleles of HLA-DQ rs7453920 were significantly increased in chronic HBV infection patients. A total of 77 (79.4%) patients were responders. Among this group, 72.7% were male, and the average age was 38.59 ±9.15 years. On evaluation of the association between polymorphisms in HLA-DQ gene and treatment response, the results indicated that response to treatment declined when patients were carrying the more unfavorable rs 7453920 GG with a response rate of 64%. Patients carrying the mutant allele AG, or the wild type allele AA were more likely to achieve a higher rate of response (84.8% and 83.3%, respectively). Conclusion: The presence of HLA-DQB2 rs 7453920-G serves as a risk factor for chronic HBV infection and treatment failure in the Egyptian population.

Upregulation of microRNA-328-3p by hepatitis B virus contributes to THLE-2 cell injury by downregulating FOXO4

BackgroundHepatitis B virus (HBV) remains a major cause of chronic hepatitis and hepatocellular carcinoma, and miRNAs play important roles in HBV pathogenesis. Our previous study has shown that miR-328-3p is upregulated in HBV-infected patients and serves as a potent predictor for the prognosis of HBV-related liver failure.MethodsHere, the role of miR-328-3p in modulating cell injury in HBV-infected liver cells THLE-2 was investigated in detail. MiR-328-3p expression was examined using qRT-PCR. The levels of pro-inflammatory cytokines were measured using ELISA. HBV RNA and HBV DNA levels were quantified. The interactions between STAT3 and miR-328-3p promoter as well as miR-328-3p and FOXO4 were analyzed using chromatin immunoprecipitation (CHIP) assay and luciferase reporter assay, respectively. THLE-2 cell injury was evaluated by examining cell viability and apoptosis.ResultsHBV promoted expression of miR-328-3p through the STAT3 signal pathway and that increasingly expressed miR-328-3p downregulated its target FOXO4, leading to the promotion of cell injury in HBV-infected liver cells THLE-2.ConclusionThese data demonstrate that HBV-STAT3-miR-328-3p-FOXO4 regulation pathway may play an important role in the pathogenesis of HBV infection.

Chronic hepatitis B infection alters peripheral immune response in women with reproductive failure.

Does hepatitis B infection affect peripheral blood immune response in women with reproductive failure? Two hundred and twenty-seven women, including 10 HBsAg+ HBeAg+ , 27 HBsAg+ HBeAg- hepatitis sero-positive women, and 190 women without HBV infection, formed the study population. Their peripheral immune responses containing lymphocyte subsets, cytokine production, expression of cell surface markers and intracellular toxicity molecules, and pregnancy outcomes were retrospectively compared. Comparing with HBsAg+ HBeAg- carriers and HBsAg- group, HBsAg+ HBeAg+ group had lower rates of CD3+ CD4+ helper T cells (31.7% vs 38.0% and 36.8%, P<0.05, respectively), but higher frequency of CD19+ B cells (17.8% vs 14.0% and 13.2%, P<0.05 and P<0.01, respectively). NK cells in HBsAg+ HBeAg+ patients showed lower cytotoxic activity than that in two other groups (P<0.05). Comparing with HBsAg- patients, HBsAg+ HBeAg+ group exhibited decreased expression of the activating receptor NKG2D (56.2% vs 66.1%, P<0.05), as well as reduced expression of granzyme B (54.8% vs 70.5%, P<0.05), perforin (49.9% vs 65.0%, P<0.05), and granulysin (52.0% vs 67.9%, P<0.01). Generally, a higher clinical pregnancy rate (85.7% vs 56.9%) and higher early miscarriage rate (33.3% vs 20.3%) were noticed in HBsAg+ HBeAg+ group than HBsAg- group. Chronic HBV infection alters peripheral immune responses by upregulating B-cell frequency, decreasing CD3+ CD4+ helper T cells, and decreasing peripheral NK function and toxicity. These may influence pregnancy outcome on HBV-infected patients, and the pathogenesis of HBV infection on pregnancy outcome deserves to be further studied.

HBeAg induces the expression of macrophage miR-155 to accelerate liver injury via promoting production of inflammatory cytokines.

Activation of Kupffer cells (KCs) induced that inflammatory cytokine production plays a central role in the pathogenesis of HBV infection. The previous studies from our and other laboratory demonstrated miRNAs can regulate TLR-inducing inflammatory responses to macrophage. However, the involvement of miRNAs in HBV-associated antigen-induced macrophage activation is still not thoroughly understood. Here, we evaluated the effects and mechanisms of miR-155 in HBV-associated antigen-induced macrophage activation. First, co-culture assay of HepG2 or HepG2.2.15 cells and RAW264.7 macrophages showed that HepG2.2.15 cells could significantly promote macrophages to produce inflammatory cytokines. Furthermore, we, respectively, stimulated RAW264.7 macrophages, mouse primary peritoneal macrophages, or healthy human peripheral blood monocytes with HBV-associated antigens, including HBcAg, HBeAg, and HBsAg, and found that only HBeAg could steadily enhance the production of inflammatory cytokines in these cells. Subsequently, miRNAs sequencing presented the up- or down-regulated expression of multiple miRNAs in HBeAg-stimulated RAW264.7 cells. In addition, we verified the expression of miR-155 and its precursors BIC gene with q-PCR in the system of co-culture or HBeAg-stimulated macrophages. Meanwhile, the increased miR-155 expression was positively correlation with serum ALT, AST, and HBeAg levels in AHB patients. Although MAPK, PI3K, and NF-κB signal pathways were all activated during HBeAg treatment, only PI3K and NF-κB pathways were involved in miR-155 expression induced by HBeAg stimulation. Consistently, miR-155 over-expression inhibited production of inflammatory cytokines, which could be reversed by knocking down miR-155. Moreover, we demonstrated that miR-155 regulated HBeAg-induced cytokine production by targeting BCL-6, SHIP-1, and SOCS-1. In conclusion, our data revealed that HBeAg augments the expression of miR-155 in macrophages via PI3K and NF-κB signal pathway and the increased miR-155 promotes HBeAg-induced inflammatory cytokine production by inhibiting the expression of BCL-6, SHIP-1, and SOCS-1.

Comparison of Laboratory Values of Prisoner and Civil Patients with Chronic Hepatitis B

OZET Objective: Since immune processes play a role in the pathogenesis of HBV infection, the immune system of the host is an important factor in the healing of the infection. The aim of the present study is to compare the laboratory findings related to hepatitis B in inmates with chronic hepatitis B, who live in a confined space and whose immune system is affected by various stress factors, and civilian chronic hepatitis B patients. Materials and Methods: The approval of the Dicle University Medical School, NonInvasive Clinical Studies Ethics Committee was obtained for the study. Inmates and civilians with hepatitis B who presented to the infectious diseases outpatient clinic between December 2010 and June 2013 were enrolled in the study. Both groups were statistically compared in terms of HBV DNA, ALT, AST and HBeAg. Results: A total of 34 inmates and 34 civilian patients were evaluated. While no difference was observed in terms of the liver enzymes, HBeAg positivity was significantly higher among the inmates. Also, a HBV DNA > 104 copies/ml was more frequently observe din the group of inmates, although the difference was statistically insignificant. Conclusion: Studies comparing chronic hepatitis B patients who are leading different lifestyles will help select the patients with priority for treatment. (Viral Hepatitis Journal 2014; 20(2): 57-60)

The role of von Willebrand factor as a biomarker of tumor development in hepatitis B virus-associated human hepatocellular carcinoma: a quantitative proteomic based study.

We report comparative plasma proteome profiles of HBV-associated HCC and nonmalignant chronic liver diseases, including chronic hepatitis B and cirrhosis. The quantification of these datasets showed altered abundance of 21 proteins in HBV-related HCC and provides a reference point for future applied and basic research. In addition, we have demonstrated that the candidate protein vWF is involved in the pathogenesis of HBV infection and replication, and also associated with clinicopathologic staging of HCC patients with HBV infection. Overall these findings provide information on the mechanism of HCC development, which may assist in the development of novel cancer and HBV therapeutic drugs.

Soluble tumor necrosis factor related apoptosis inducing ligand (sTRAIL) and clinical outcome of HBV infection in human

To explore the role of sTRAIL in the pathogenesis of HBV infection in human being. sTRAIL in 153 patients' sera was examined with ELISA. Correlations between sTRAIL and liver functional parameters were analysed. The levels of sTRAIL in patients with various clinical types of hepatitis B as well as primary hepatocellular carcinoma were all higher than that in normal persons and became almost normal in recovering stage cases. In acute and chronic HBV infection, sTRAIL level was negatively correlated with ALT, AST and total bilirubin levels, and positively correlated with serum albumin. The results indicated that higher level of sTRAIL expression is correlated with liver damage, and apoptosis induced by sTRAIL is one of the mechanisms of liver damage in HBV infection.

Nature and display of hepatitis B virus envelope proteins and the humoral immune response

The pattern of display of envelope proteins on HBV indicates that the preS domains have an important role in virus assembly and secretion. Furthermore sites of interaction with the membrane of hepatocytes and of other cells which are susceptible to infection have been identified within the preS1 and preS2 protein domains. These observations support the concept that these sequences represent the virus attachment sites for the host cell membrane. The nature of the cellular receptors involved in this binding has not yet been fully clarified. Several B and T cell epitopes, which evoke antibody and cellular response in humans, have been identified within the preS1 and preS2 protein domains. The immune response to some of these determinants seems to be particularly relevant in virus neutralization and in termination of virus replication. Their exact characterization is needed for possible inclusion in recombinant HB vaccines, to further increase their efficacy. The immune response to preS may also be involved in the pathogenesis of liver disease, as preS1 and preS2 epitopes are recognized by cytotoxic T lymphocytes during chronic infection and after HB vaccination. These findings need to be extended further and may provide new important information on the pathogenesis of HBV infection.