Hepatitis B Virus Chronic Hepatitis Research Articles

Targeted viral adaptation generates a simian-tropic hepatitis B virus that infects marmoset cells

Hepatitis B virus (HBV) only infects humans and chimpanzees, posing major challenges for modeling HBV infection and chronic viral hepatitis. The major barrier in establishing HBV infection in non-human primates lies at incompatibilities between HBV and simian orthologues of the HBV receptor, sodium taurocholate co-transporting polypeptide (NTCP). Through mutagenesis analysis and screening among NTCP orthologues from Old World monkeys, New World monkeys and prosimians, we determined key residues responsible for viral binding and internalization, respectively and identified marmosets as a suitable candidate for HBV infection. Primary marmoset hepatocytes and induced pluripotent stem cell-derived hepatocyte-like cells support HBV and more efficient woolly monkey HBV (WMHBV) infection. Adapted chimeric HBV genome harboring residues 1–48 of WMHBV preS1 generated here led to a more efficient infection than wild-type HBV in primary and stem cell derived marmoset hepatocytes. Collectively, our data demonstrate that minimal targeted simianization of HBV can break the species barrier in small NHPs, paving the path for an HBV primate model.

335.2: Long-term Outcomes of Liver Transplantation Using Grafts From Donors With Active Hepatitis B virus Replication: A Multicenter Cohort Study

Background: Liver grafts from donors with hepatitis B infection contributed to expanding the donor pool under the Hepatitis B immunoglobulin (HBIG) and antiviral agents (NA: Nucleos(t)ide analogs) in the hepatitis B virus (HBV) endemic area. The purpose of this study is to describe the long-term outcome of liver transplantation (LT) using grafts from donors with active and chronic hepatitis B virus infection. Methods: Between January 2000 and April 2019, 2260 liver transplants (LTs) were performed at Seoul National University (SNU) Hospital, SNU Bundang Hospital (SNUBH), and Seoul Metropolitan Government-SNU Boramae Hospital. Twenty-six (1.2%) grafts from donors with HBsAg (+), HBeAb (+), or HBV DNA (+) were classified as active and chronic HBV hepatitis grafts and retrospectively reviewed. The demographics of donors and recipients, as well as the outcomes of transplantation, were analyzed. HBV reactivation has been defined as an increase in viral DNA in HBsAg (+) grafts and seroconversion to HBsAg positive grafts in chronic hepatitis grafts. Additionally, we used the chronic HBV infection stage to evaluate and manage recipients who received HBV-infected grafts. Results: Sixteen LT were performed on deceased donors using active HBsAg (+) grafts. Ten living donor LT were performed using inactive HBV grafts; eight patients with inactive hepatitis; HBsAg (-), HBcAb (+), and HBV DNA (+), and two patients with chronic HBV hepatitis with seroconversion; HBsAg (-), HBsAb (+), and HBeAg (+) (Figure 1). The recipients were aged 59.0 ± 10.3 years and had a MELD score of 19.9 ± 8.4. The mean duration of follow-up was 82.6 ± 60.1 months. Depending on the donor and recipient’s serology, NA and HBIG were administered during the perioperative period. Deaths (n=8) occurred between 2.0 and 47.3 months following LT. All deaths were reported in DDLT. When compared with LT using grafts without HBV, LT using HBV infected grafts did not show any significant difference in patient survival (30.8% vs. 18.6%, p=0.247) (Figure 2). The most common causes of death were infection (n=4) and HCC recurrence (n=3). All recurred HCC patients died of cancer. HBV reactivation was identified in 1 patient but resolved spontaneously without additional management. All 10 LDLT recipients survived and were in good condition during follow-up. Survivors were in inactive or resolved status for HBV infection under the HBIG and NA. No graft failure was observed. Fourteen patients followed-up more than 5 years were stable and no increase in HCC recurrence rate was observed 5 years after transplantation. Conclusion: Considering their long-term outcomes, liver grafts with active and chronic HBV infection can be safely used for LT in HBV endemic area.

Effectiveness of a screening program for HBV, HCV, and HIV infections in African migrants to Sicily.

Migrants from Africa are vulnerable to viral infections during their journey. Migrants who arrived in western Sicily were offered early screening for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infection. A questionnaire was administered to evaluate risk factors, and antiviral therapy was offered to subjects with active infection. A multiple regression analysis and adjusted odds ratio were obtained to evaluate risk factors. Overall, 2,639 of 2,751 (95.9%) migrants who arrived between 2015 and 2017 accepted screening and 1,911 (72.4%) completed the questionnaire. HBsAg was positive in 257 (9.7%) migrants, 24 (0.9%) were anti-HCV positive and 57 (2.2%) had HIV infection. The prevalence of HBV infection was higher in women (aOR 2.47,95%CI 1.90-3.20),p=0.003) and in people who endured physical and/or sexual violence (aOR 2.24,95%CI 1.87-3.55,p<0.001), while HIV infection was more frequent in women (aOR 5.40,95%CI 3.09-9.43, p <0.001) who were in Libya for a long period (aOR 5.66,95%CI 2.90-10.70,p=0.004) and endured physical and/or sexual violence (aOR 14.77,95%CI 8.34-22.11,p<0.001). Being older than 18 was associated with HCV infection (p<0.001). Overall, 77% of 57 subjects with HIV infection were retained in care, 79% of 70 chronic HBV hepatitis cases started nucleot(s)ide analogues and 61% of 18 HCV-RNA positive cases received direct-acting antiviral therapy. These findings evidence the effectiveness and feasibility of infectious disease screening programs for migrants.

Non-invasive Assessment of Subclinical Renal Parenchymal Changes in Chronic Hepatitis B Virus By T1 Mapping Magnetic Resonance Imaging.

Background:Renal parenchymal changes are seen in chronic hepatitis B virus (HBV) infection, and its disease diagnosis should be confirmed by renal biopsy, which is an invasive technique. Apparent-T1 mapping magnetic resonance imaging (MRI) is an established imaging technique that assesses subclinical tissue injury without using a contrast agent.Aims:To investigate the early stage subclinical renal changes without apparent renal dysfunction in patients with chronic HBV infection by renal apparent-T1 mapping MRI.Study Design:A cross-sectional study.Methods:This study included 45 participants with normal kidney function, wherein 25 have biopsy-proven chronic HBV hepatitis and 20 are healthy individuals. Liver and kidney biochemical tests were performed within 1 month before the MRI scan, and the estimated glomerular filtration rate was calculated by diet modification in renal disease formula. Breath-hold, electrocardiogram-gated Modified Look-Locker Imaging sequence was acquired in the coronal plane without contrast agent administration. Apparent-T1 mapping value was measured by manually drawing a region of interest in six points for both kidneys by two observers. Apparent-T1 mapping values were compared between the two groups.Results:The mean apparent-T1 mapping values of the kidneys were significantly higher in patients with chronic HBV infection compared to the control group (1445 ± 129 ms vs. 1306 ± 115 ms, P = 0.003). Inter-class correlation coefficient measurement analysis showed excellent agreement.Conclusion:Renal apparent-T1 mapping MRI may help show the early stage of renal parenchymal disease without apparent renal dysfunction in chronic HBV infection.

Outcomes of acute hepatitis B virus (HBV) in HIV infection with and without HBV-active antiretroviral therapy.

Men with acute hepatitis B virus (HBV) infection in the Multicenter AIDS Cohort Study from 1985 to 2013 had serological testing to determine proportions with HBV recovery or chronic hepatitis B (CHB). A similar proportion of men without human immunodeficiency virus (HIV) and men with HIV receiving HBV-active antiretroviral therapy (ART) developed CHB [8.2%, 95% confidence interval (CI) 3.8-15.0% vs. 7.7%, 95% CI 2.00-36.0%]. In contrast, 17.5% (95% CI 8.7-29.9%) of men living with HIV, not on HBV-active ART developed CHB. HBV-active ART protects against developing CHB.

Circulating microRNAs as non-invasive biomarkers for hepatitis B virus liver fibrosis.

Viruses can alter the expression of host microRNAs (MiRNA s) and modulate the immune response during a persistent infection. The dysregulation of host MiRNA s by hepatitis B virus (HBV) contributes to the proinflammatory and profibrotic changes within the liver. Multiple studies have documented the differential regulation of intracellular and circulating MiRNA s during different stages of HBV infection. Circulating MiRNA s found in plasma and/or extracellular vesicles can integrate data on viral-host interactions and on the associated liver injury. Hence, the detection of circulating MiRNA s in chronic HBV hepatitis could offer a promising alternative to liver biopsy, as their expression is associated with HBV replication, the progression of liver fibrosis, and the outcome of antiviral treatment. The current review explores the available data on miRNA involvement in HBV pathogenesis with an emphasis on their potential use as biomarkers for liver fibrosis.

Influence of PON1 gene polymorphisms (rs662 and rs854560) on the chronicity of HBV infection

Hepatitis B is a major health problem in Turkey as it is all over the world. Therefore, it is noteworthy to understand the genetic background of hepatitis B virus (HBV)-infection. In order to investigate the effect of the PON1 gene in different clinical conditions of HBV infection, we analyzed common Q192R (rs662) and L55 M (rs854560) polymorphisms in HBV-infected individuals through PCR and RFLP technics. The present study involved 59 HBV carriers (chronic inactive hepatitis B patients) and 60 chronic active hepatitis B patients. The chi-square test was used to compare allele and genotype frequencies of chronic active hepatitis patients and HBV carriers. Any statistically significant diversity was not observed between HBV carriers and chronic active hepatitis B patients according to genotype and allele frequencies of PON1 gene polymorphisms. However, chronic active hepatitis patients and HBV carriers showed statistically significant diversities in terms of combined genotypes of Q192R and L55 M polymorphisms. According to results of our study, a possible relationship could be suggested between combined genotypes of Q192R and L55 M polymorphisms of PON1 gene and chronicity of HBV infection in Turkish population.

Association of STAT3 and STAT4 polymorphisms with susceptibility to chronic hepatitis B virus infection and risk of hepatocellular carcinoma: a meta-analysis.

Background: It has been reported that polymorphisms of signal transducer and activator of transcription (STAT) 3 and STAT4 might be associated with susceptibility to hepatitis B virus (HBV) infection and risk of chronic hepatocellular carcinoma (HCC). Owing to limitation of sample size and inconclusive results, we conducted a meta-analysis to clarify the association. Methods: We identified relevant studies by a systematic search of Medline/PubMed, Embase, Web of Science and the Cochrane Library up to 20 February 2019. The strength of the association measured by odds ratios (OR) with 95% confidence intervals (CIs) was studied. All the statistical analyses were conducted based on Review Manager 5.3 software. Results: A total of 5242 cases and 2717 controls from five studies were included for the STAT3 polymorphism, 5902 cases and 7867 controls from nine studies for the STAT4 polymorphism. Our results suggested that STAT3 rs1053004 polymorphism was a significant risk factor of chronic HBV infection (C vs. T: OR = 1.17, 95% CI: 1.07–1.29, PA=0.0007; CC + CT vs. TT: OR = 1.38, 95% CI: 1.09–1.76, PA=0.008). Validation with all the genetic models revealed that rs7574865 polymorphism of STAT4 gene was closely associated with chronic HBV infection (PA<0.01) and chronic hepatitis B (CHB)-related HCC (PA<0.05). Meanwhile, the authenticity of the above meta-analysis results was confirmed by trial sequential analysis (TSA). Conclusions: The meta-analysis showed that STAT3 rs1053004 polymorphism may be the risk for developing chronic HBV infection but not associated with HCC. The present study also indicates that STAT4 rs7574865 polymorphism increased the risk of chronic HBV infection and HCC.

Potential circulating biomarkers of circulating chemokines CCL5, MIP-1\u03b2 and HA as for early detection of cirrhosis related to chronic HBV (hepatitis B virus) infection

BackgroundDue to no clinical symptoms in the compensated stage of cirrhosis, it is usually diagnosed when decompensated complications occur. In this study, the noninvasive circulating biomarkers for early detection to compensated stage of cirrhosis in patients with chronic HBV (hepatitis B virus) infection was explored.MethodsAccording to the Guideline of Prevention and Treatment of Chronic Hepatitis B (2015 Update), 78 patients with CHB (chronic hepatitis B) were divided into mild group, moderate-to-advanced group, while 73 patients with HBV-related cirrhosis were divided into compensated group and decompensated group. Nineteen cytokines and chemokines, four serum liver fibrosis markers were measured using chemiluminescence. The expression of CCL5 in liver tissue was determined with immunohistochemistry.ResultsThe CCL5 expression level in serum increased in CHB patients with aggravated liver injury and significantly decreased in cirrhosis patients with advanced liver fibrosis. ROC analysis revealed that the serum levels of CCL5, HA and MIP-1β were effective in distinguishing patients with cirrhosis from patients with CHB, especially for CCL5. Increasing serum level of CCL5 in CHB patients was severely associated with disease progression.ConclusionsThe serum levels of CCL5, HA and MIP-1β maybe used to distinguish cirrhosis from CHB patients, moreover, CCL5 was the most reliable marker. The increasing serum levels of CCL5 were significantly related to disease progression in CHB patients.

Correlation between serum Hcy level and severity of chronic HBV hepatitis

Abstract Objective The aim of this work was to investigate the serum homocysteine (Hcy) level and severity of hepatitis B virus (HBV). Methods 72 patients with chronic HBV and 28 healthy controls were included in this work. Of the included 72 chronic HBV hepatitis patients, 20 patients had mild disease, 31 had moderate disease and 21 had severe disease. The serum homocysteine (Hcy), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) were examined in both HBV hepatitis and control patients. Results Significant statistical difference was observed for serum Hcy, ALT, AST and TBIL in different groups (p&lt;0.05). The serum Hcy, ALT, AST and TBIL in the severe group were significantly higher than those of other groups with statistical difference (p&lt;0.05); significant correlation was observed between serum Hcy and AST in the moderate (r=0.43, p&lt;0.05) and severe disease groups (r=0.63, p&lt;0.05). However, the correlation between Hcy and ALT, and Hcy andTBIL were not statistically significant in any group (p&gt;0.05). Conclusion The serum Hcy level in patients with hepatitis B reflects the damage to the of liver. The continuous increase of serum Hcy level can be regarded as a risk factor for the progression of hepatitis, and it can be used as serological marker for clinical diagnosis, treatment and prognosis.

Screening for retroviruses and hepatitis viruses using dried blood spots reveals a high prevalence of occult hepatitis B in Ghana.

Background:Recent advances in antiviral therapy show potential for a cure and/or control of most human infections caused by hepatitis viruses and retroviruses. However, medical success is largely dependent on the identification of the large number of people unaware of these infections, especially in developing countries. Dried blood spots (DBS) have been demonstrated to be a good tool for collecting, storing and transporting clinical specimens from rural areas and limited-resource settings to laboratory facilities, where viral infections can be more reliably diagnosed.Methods:The seroprevalence and virological characterization of hepatitis B virus (HBV) and hepatitis C virus (HCV), as well as human retroviruses (HIV-1, HIV-2, human T-cell leukaemia virus type 1 [HTLV-1] and human T-cell leukaemia virus type 2 [HTLV-2]), were investigated in clinical specimens collected from DBS in Ghana.Results:A total of 305 consecutive DBS were collected. A high prevalence of chronic HBV (8.5%) and occult hepatitis B (14.2%) was found, whereas rates were lower for HIV-1, HTLV-1 and HCV (3.2%, 1.3% and 0.6%, respectively). HIV-2 and HTLV-2 were absent. CRF02_AG was the predominant HIV-1 subtype, whereas genotype E was the most frequent HBV variant.Conclusions:DBS are helpful in the diagnosis and virological characterization of hepatitis and retrovirus infections in resource-limited settings. The high rate of hepatitis B in Ghana, either overt or occult, is noteworthy and confirms recent findings from other sub-Saharan countries. This should encourage close clinical follow up and antiviral treatment assessment in this population, as well as universal HBV vaccine campaigns.

Comparison of Hepatitis B Virus Infection in HIV-Infected and HIV-Uninfected Participants Enrolled in a Multinational Clinical Trial: HPTN 052

Data comparing hepatitis B virus (HBV) infection in HIV-infected [HIV(+)], and HIV-uninfected [HIV(-)] individuals recruited into the same study are limited. HBV infection status and chronic hepatitis B (cHB) were characterized in a multinational clinical trial: HIV Prevention Trials Network (HPTN 052). HBV infection status at enrollment was compared between HIV(+) (N = 1241) and HIV(-) (N = 1232) from 7 HBV-endemic countries. Hepatitis B e antigen and plasma HBV DNA were determined in cHB. Median CD4, median plasma HIV RNA, and prevalence of transaminase elevation were compared in HIV(+) with and without cHB. Significance was assessed with χ, Fisher exact, and median tests. Among all participants, 33.6% had HBV exposure without cHB (8.9% isolated HBV core antibody, "HBcAb"; 24.7% HBcAb and anti-HB surface antibody positive, "recovered"), 4.3% had cHB, 8.9% were vaccinated, and 53.5% were uninfected. Data were similar among HIV(+) and HIV(-) except for isolated HBcAb, which was more prevalent in HIV(+) than HIV(-) [10.1% vs. 7.7%, P = 0.046]. Median HBV DNA trended higher in HIV(+) than in HIV(-). In HIV(+) with cHB versus those without cHB, transaminase elevations were more prevalent (alanine aminotransferase ≤ grade 2, 12% vs. 5.2%, P = 0.037; aspartate aminotransferase ≤ grade 2, 26% vs. 6.0%, P < 0.001), CD4 trended lower, and HIV RNA was similar. HBV infection status did not differ by HIV infection status. HIV co-infection was associated with isolated HBcAb and a trend of increased HBV DNA. In HIV, cHB was associated with mild transaminase elevations and a trend toward lower CD4.

Immunity and Fibrogenesis: The Role of Th17/IL-17 Axis in HBV and HCV-induced Chronic Hepatitis and Progression to Cirrhosis.

Cirrhosis is a common final pathway for most chronic liver diseases; representing an increasing burden worldwide and is associated with increased morbidity and mortality. Current evidence has shown that, after an initial injury, the immune response has a significant participation in the ongoing damage, and progression from chronic viral hepatitis (CVH) to cirrhosis, driving the activation and maintenance of main fibrogenic pathways. Among immune deregulations, those related to the subtype 17 of T helper lymphocytes (Th17)/interleukin-17 (IL-17) axis have been recognized as key immunopathological and prognostic elements in patients with CVH. The Th17/IL-17 axis has been found involved in several points of fibrogenesis chain from the activation of stellate cells, increased expression of profibrotic factors as TGF-β, promotion of the myofibroblastic or epithelial–mesenchymal transition, stimulation of the synthesis of collagen, and induction of imbalance between matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). It also promotes the recruitment of inflammatory cells and increases the expression of proinflammatory cytokines such as IL-6 and IL-23. So, the Th17/IL-17 axis is simultaneously the fuel and the flame of a sustained proinflammatory and profibrotic environment. This work aims to present the immunopathologic and prognostic role of the Th17/IL-17 axis and related pathways in fibrogenesis and progression to cirrhosis in patients with liver disease due to hepatitis B virus (HBV) and hepatitis C virus (HCV).

Interaction effects among IFN-γ+874, IL-2-330, IL-10-1082, IL-10-592 and IL-4-589 polymorphisms on the clinical progression of subjects infected with hepatitis B virus and/or hepatitis C virus: a retrospective nested case–control study

BackgroundThe natural outcomes of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections vary considerably among individuals The infection may heal naturally, or patients may succumb to chronic liver...

Characterization and clinical application of a monoclonal antibody to hepatitis B virus large surface proteins

The pre-S domain of large surface proteins (LHBs) is thought to be associated with the infectious and sub-infectious particles of hepatitis B virus (HBV), and the quantitative measurement of the LHBs has become the critical serological assay for management of chronic HBV hepatitis. Here, we generated a monoclonal antibody with improved specificity and efficacy for both the native form and the glycosylated, full-length recombinant pre-S large protein, and tested it in clinical applications. We recruited 573 HBV patients and detect HBV large envelope proteins and the circulating viral load. We then studied the relationship between LHBs and HBV DNA in follow-up studies of 78 patients who received Adefovir antiviral treatment. We found that there was no significant difference between the rate of positive HBV DNA and the rate of positive LHBs. The levels of both HBV DNA and LHBs declined during the antiviral treatment, although the levels of LHBS decline later than the level of viremia.do. Furthermore, patients with 18 consecutive months of positive LHBs were able to obtain HBV DNA conversion, even if they continued to receive the antiviral treatment. Our study demonstrates that the level of LHBs can efficiently reflect the replication status of the virus in patients with HBeAg-negative diseases, and the LHB assay support the HBV test. Furthermore, examining the combination of LHBs and HBV DNA has important clinical implications for monitoring the effectiveness of the antiviral treatments.

Effect of prior hepatitis B virus exposure on long-term risk of liver-related events after liver transplantation.

To characterize the risk of liver-related events and death in hepatitis B virus (HBV)-exposed liver transplantation (LT) recipients. Retrospective review was performed in all adults who underwent LT between January 1995 through December 2010 at the Johns Hopkins Hospital. Recipients with graft failure or death within 14 d of LT or missing HBV status were excluded, leaving 575 individuals for analysis. Patients were classified according to HBV exposure status: Unexposed, Resolved HBV, Chronic HBV, or hepatitis B core antibody (anti-HBc) seropositive liver donor. Compared with HBV-unexposed patients, the relative hazard of combined liver-related events (rejection, cirrhosis, re-transplantation) and death after LT was not increased in patients with a baseline history of resolved HBV infection or chronic hepatitis B. Using anti-HBc seropositive donors also did not increase the risk of liver-related events, death, or composite events (all p ≥ 0.05). However, hepatitis C was associated with liver-related events [adjusted hazard ratio (aHR), 1.59; 95% confidence interval (CI), 1.00-2.52], and blacks had a higher risk of death (aHR, 1.50; 95% CI, 1.01-2.22). LT of patients with prior HBV exposure or use of anti-HBc seropositive donors is not associated with increased risk of liver-related events or death.

HLA‐E polymorphism and soluble HLA‐E plasma levels in chronic hepatitis B patients

Chronic hepatitis B virus (HBV) infection occurs in association to a deregulation of immune system. Human leukocyte antigen E (HLA-E) is an immune-tolerant nonclassical HLA class I molecule that could be involved in HBV progression. To measure soluble (s) HLA-E in patients with chronic HBV hepatitis (CHB). We tested the potential association of HLA-E*01:01/01:03 A > G gene polymorphism to CHB. Our cohort consisted of 93 Tunisian CHB patients (stratified in CHB with high HBV DNA levels and CHB with low HBV DNA levels) and 245 healthy donors. Plasma sHLA-E was determined using enzyme-linked immunosorbent assay (ELISA). Genotyping was performed using polymerase chain reaction sequence-specific primer. No association between HLA-E*01:01/01:03 A > G polymorphism and HBV DNA levels in CHB patients was found. G/G genotype is less frequent in CHB patients without significance. sHLA-E is significantly enhanced in CHB patients compared with healthy controls (P = 0.0017). Stratification according to HBV DNA levels showed that CHB patients with low HBV DNA levels have higher sHLA-E levels compared with CHB patients with high HBV DNA levels. CHB patients with G/G genotype have enhanced sHLA-E levels compared with other genotypes (P = 0.037). This significant difference is maintained only for CHB women concerning G/G genotypes (P = 0.042). Finally, we reported enhanced sHLA-E in CHB patients with advanced stages of fibrosis (P = 0.032). We demonstrate, for the first time, the association of sHLA-E to CHB. Owing to the positive correlation of HLA-E*01:01/01:03 A > G polymorphism and the association of sHLA-E to advanced fibrosis stages, HLA-E could be a powerful predictor for CHB progression. Further investigations will be required to substantiate HLA-E role as a putative clinical biomarker of CHB.

MicroRNA panels as disease biomarkers distinguishing hepatitis B virus infection caused hepatitis and liver cirrhosis

An important unresolved clinical issue is to distinguish hepatitis B virus (HBV) infection caused chronic hepatitis and their corresponding liver cirrhosis (LC). Recent research suggests that circulating microRNAs are useful biomarkers for a wide array of diseases. We analyzed microRNA profiles in the plasmas of a total of 495 chronic hepatitis B (CHB) patients, LC patients and healthy donors and identified 10 miRNAs that were differentially expressed between CHB and LC patients. Our logistic models show that three panels of miRNAs have promising diagnostic performances in discriminating CHB from LC. Blinded tests were subsequently conducted to evaluate the diagnostic performances in clinical practice and a sensitivity of 85% and specificity of 70% have been achieved in separating CHB from LC pateints. The expression levels of some circulating miRNAs were significantly correlated with HBV DNA load and liver function, such as prothrombin activity (PTA) and levels of alanin aminotransferase (ALT), albumin (ALB) and cholinesterase (CHE). Our results provide important information for developing novel diagnostic tools for distinguishing chronic HBV hepatitis and their corresponding cirrhosis.

IL-35 inhibits HBV antigen-specific IFN-γ-producing CTLsin vitro

Interleukin (IL)-35 is an inhibitory cytokine consisting of IL-12A and Epstein-Barr virus-induced gene 3 (Ebi3) and is required by regulatory T-cells (Tregs) for maximal activity. During chronic hepatitis B virus (HBV) infection, Tregs have immunosuppressive effects on HBV-specific T helper (Th) cells, yet little is known about the complex regulation of Tregs and their contribution to the inadequate immune system response to the virus. In the present study, we investigated whether IL-35 is involved in HBV-related cellular immune responses. Cluster of differentiation (CD)4(+) T-cells from peripheral blood were derived from healthy volunteers, resolved HBV individuals and chronic active hepatitis B patients and stimulated with CD3/28-conjugated beads. We analysed mRNA and protein levels of IL-35 and assessed the inhibitory effect of IL-35 on HBV core antigen-specific cytotoxic T lymphocytes (CTLs), dendritic cells (DCs) and effector T-cells (Teffs). Correlation analyses between liver inflammation and HBV DNA load were conducted. Results show that chronic HBV patients harbour significantly higher levels of Ebi3 mRNA and protein in CD4(+) T-cells compared with healthy volunteers and resolved HBV individuals. IL-35 suppressed the proliferation of HBV antigen-specific CTLs and interferon (IFN)-γ production invitro. Ex vivo, IL-35 decreased the proliferation of CD4(+)CD45RA(+) naïve T-cells, especially in CD4(+)CD25(-)CD45RA(+) naïve Teffs. IL-35 inhibited the expansion of CD11c(+) DCs. Our data indicate that IL-35 is highly expressed in chronic HBV CD4(+) T-cells and plays an important role in the inhibition of the cellular immune response in chronic HBV.

Downregulation of immunosuppressive environment in patients with chronic HBV hepatitis on maintained remission.

Downregulation of immunosuppressive environment in patients with chronic HBV hepatitis on maintained remission.