Elimination Of Hepatitis B Virus Research Articles

CCR2+TREM-1+ monocytes promote natural killer T cell dysfunction contributing towards HBV disease progression.

Natural killer T (NKT) cells are amongst the most important innate immune cells against hepatitis B virus (HBV) infection. Moreover, previous studies have shown that HBV infection induced TREM-1+ expression in monocyte and secretion of inflammatory cytokines. Thus, this prompted us to elucidate the role of TREM-1+ monocytes in regulating the function of iNKT cells. Ninety patients and 20 healthy participants were enrolled in the study. The percentage and phenotype of iNKT cells and TREM-1+ monocytes were measured in the peripheral blood of healthy controls (HC), patients with chronic HBV infection (CHB), HBV-related liver cirrhosis (LC), and HBV-related acute-on-chronic liver failure (ACLF) via flow cytometry. Moreover, co-culture experiments with iNKT cells and TREM-1 overexpressing THP-1 cells were performed to determine the role of TREM-1 in the regulation of NKT cell function. We observed that the percentage of iNKT cells and CD4-iNKT cells gradually decreased, whereas the percentage of CCR2+TREM-1+ monocytes increased with the progression of the disease. In addition, activation of the TREM-1 signaling pathway induced the secretion of inflammatory cytokines leading to pyroptosis of iNKT cells and secretion of IL-17 contributing towards disease progression. Therefore, this study suggests that blocking the activation of TREM-1 in monocytes could promote the elimination of HBV by inhibiting pyroptosis of iNKT cells and restoring their function. However, further studies are required to validate these results that would help in developing new treatment strategies for patients with HBV infections.

Global elimination of HBV: Is it really achievable?

Hepatitis B virus (HBV) infection is a major cause of premature death worldwide. In 2016, the World Health Organization (WHO) called for HBV elimination and set up very ambitious elimination targets. The development of effective vaccines, accurate diagnostic tools and safe antiviral drugs make HBV elimination a realistic goal. However, the most constrained-resource regions, which bear the highest burden of HBV, are facing major challenges in implementing strategies to reduce HBV incidence and mortality. Developing simplified approaches adapted to resource-limited settings and scaling up interventions for the prevention and control of HBV globally are urgently needed. Whether HBV elimination will be achieved in an equitable manner and in a reasonable timeframe remains highly uncertain.

Evaluation of the Efficacy and Safety of Tenofovir Disoproxil Fumarate in Intercepting Mother-to-Child Transmission of Hepatitis B Virus.

Vertical transmission of hepatitis B virus (HBV), especially in Asia, is a key target in the global elimination of HBV. This study assessed the effects of tenofovir disoproxil fumarate (TDF) in pregnant women for mother-to-infant transmission of HBV. A total of 122 pregnant women at our hospital met the inclusion criteria for high HBV DNA viral loads. They were randomly divided into TDF-treatment (n=70) and placebo (n=52) groups. Maternal liver function and serum HBV DNA load were tested before and after treatment. Clinical and laboratory data of infants were assayed at delivery and 7-months post-partum visit and compared between the two groups. There was no difference in clinical characteristics of participants between the two groups. There were no significant differences in liver function markers, including alanine aminotransferase, total bilirubin, blood creatinine, and blood urea nitrogen levels before and after TDF treatment. The serum HBV DNA viral load of the TDF-treated group became significantly lower than those of the control group and their own pre-medication levels. Infants showed no significant difference in body growth, including weight, height, head size, and five-min Apgar score. At 7 months after birth, 94.29% of infants in the TDF group and 86.54% of control-group infants had protective HBsAb levels ≥ 10 mIU/ml (p>0.05). The HBV infection rate of infants in the TDF-treated group was lower than that in the non-treated group. In high-HBV-DNA-load pregnant women, TDF administered from 28 weeks gestational age to delivery was associated with a lower risk of mother-to-infant transmission of HBV.

Antagonism Between Gut Ruminococcus gnavus and Akkermansia muciniphila Modulates the Progression of Chronic Hepatitis B

A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s)triggering IA entry and HBe-SC in the natural history of CHB. To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n= 102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed. Ruminococcus gnavus was the most abundant species in CHB patients in the IT phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with alanine aminotransferase flares, HBeAg loss, and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients because R gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R gnavus to allow HBV elimination. R gnavus and A muciniphila play opposite roles in HBV infection. A muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies.

Retrospective cohort study assessing coverage, uptake and associations with hepatitis B vaccination among females who engage in sex work attending sexual health services in England between 2015 and 2019

ObjectivesFemales who engage in sex work (FSW) are at high risk of hepatitis B virus (HBV) and are eligible for HBV vaccination. The objective of this analysis was to explore...

The risk of mother-to-child transmission of hepatitis B virus infection in Ethiopia: A systematic review and meta-analysis.

Mother-to-child transmission (MTCT) of hepatitis B virus (HBV) is a predominant route of infection for children in Ethiopia. No study has so far reported a nationwide estimate of the risk of MTCT of HBV. We conducted a meta-analysis of surveys and estimated the pooled risk of MTCT of HBV in the context of human immunodeficiency virus (HIV) infection. We searched PubMed, EMBASE, Web of Science, Africa Index Medicus, and Google Scholar databases for peer-reviewed articles. The pooled risk of MTCT of HBV was estimated using the DerSimonian-Laird technique with logit transformed proportions and statistical heterogeneity was estimated using I2 statistic, which was explored by subgroup and meta-regression analyses. The overall pooled risk of MTCT of HBV in Ethiopia was 25.5% (95% CI, 13.4%-42.9%). In women without HIV infection, the risk of MTCT of HBV was 20.7% (95% CI 2.8%-70.4%), and 32.2% (95% CI 28.1%-36.7%) in women with HIV infection. After excluding the outlier study, the risk of MTCT of HBV in studies that included only HIV negative women was 9.4% (95% CI, 5.1%-16.6%). The risk of MTCT of HBV in Ethiopia widely varied by HBV/HIV coinfection. A sustainable control and elimination of HBV in Ethiopia requires improved access to birth-dose HBV vaccine and implement immunoglobulin prophylaxis for exposed infants. Given the limited health resources in Ethiopia, prenatal antiviral prophylaxis integrated with antenatal care may be a cost-effective approach to significantly reduce the risk of MTCT of HBV.

Prevalence of hepatitis B virus infection and effects of service charges on notification among pregnant women attending antenatal care at General Hospital, Otukpo, Nigeria

Objectives: Hepatitis B virus (HBV) infection is a global public health problem, even though its prevalence is disproportionately high in resource-limited countries, it is still under-reported. Mother-to-child transmission is a major route of HBV transmission in an endemic region like sub-Saharan Africa. This study assessed the prevalence of HBV infection and the effect of service charge on hepatitis B surface antigen (HBsAg) disease notification among pregnant women who attended the antenatal clinic at General Hospital, Otukpo, Benue State, Nigeria. Materials and Methods: A retrospective cohort study with convenient sampling techniques were used for all pregnant women enrolled for antenatal care (ANC) within the reviewed period. Chi-square (χ2) test was used for the test of association between the independent variable and the main outcome of the study, with statistical significance set at P = 5%. Results: Of the total 1144 cases reviewed, 843 (73.7%) were tested for human immunodeficiency virus (HIV) and 301 (26.3%) were tested for HBsAg. The test for HIV was free while that of HBsAg was done out of pocket expenses. The majority of the women were between 25 and 30 years with a mean age of 25 ± 9.54 years. The seropositive rate for HIV was 2.4% (n = 20) while that of HBsAg was 5.6% (n = 17). The relationship between underreporting of positive and negative cases of HBsAg and service charges was statistically significant (P < 0.005). Conclusion: To achieve the global goal of elimination of HBV and, or reducing the prevalence of HBsAg in general population, the free opt-in screening just like in the case of HIV must be adopted for all pregnant women accessing ANC in public health facilities. This will inform both prevention, control, and antiviral management intervention strategies.

Hepatitis B core-related antigen: a novel and promising surrogate biomarker to guide anti-HBV therapy.

The current requirement for biomarkers to detect hepatitis B virus (HBV) infection is polarized. One is a fully-automated and highly sensitive measurement system; the other is a simple system for point-of-care testing (POCT) in resource-limited areas. Hepatitis B core-related antigen (HBcrAg) reflects intrahepatic covalently closed circular DNA and serum HBV DNA. Even in patients with undetectable serum HBV DNA or HBsAg loss, HBcrAg may remain detectable. Decreased HBcrAg levels are associated with reduction of the occurrence of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). Recently, a fully-automated, novel high-sensitivity HBcrAg assay (iTACT-HBcrAg, cut-off value: 2.1 log U/mL) has been developed. This attractive assay has been released in Japan very recently. iTACT-HBcrAg can be useful for monitoring HBV reactivation and prediction of HCC occurrence, as an alternative to HBV DNA. Moreover, monitoring HBcrAg may be suitable for determining the therapeutic effectiveness of approved drugs and novel drugs under development. Presently, international guidelines recommend anti-HBV prophylaxis for pregnant women with high viral loads to prevent mother-to-child transmission of HBV. However, >95% of HBV-infected individuals live in countries where HBV DNA quantification is not available. Worldwide elimination of HBV needs the scaling-up of examination and medication services in resource-limited areas. Based on this situation, a rapid and easy HBcrAg assay as a POCT is valuable. This review provides the latest information regarding the clinical use of a new surrogate marker, HBcrAg, in HBV management, based on iTACT-HBcrAg or POCT, and introduces novel agents targeting HBV RNA/protein.

Exosomes from Ub‑HBcAg‑overexpressing dendritic cells induce T‑lymphocyte differentiation and enhance cytotoxic T‑lymphocyte activity.

Hepatitis B virus (HBV) infection is a major public health concern. The clearance of HBV may involve cytotoxic T-lymphocyte (CTL) activity and T helper type 1 reactions. Exosomes generated from dendritic cells (DCs) can induce immunological responses capable of eradicating viruses. However, exosomes loaded with antigens have not yet demonstrated therapeutic potential in HBV infection. Therefore, the present study aimed to investigate the antiviral effects of DC-derived exosomes (Dexs) loaded with ubiquitinated HBV core antigen (Dexs-Ub-HBcAg). Murine bone marrow-derived DCs were loaded with a recombinant lentivector encoding the ubiquitinated form of HBcAg. High-purity Dexs were generated using differential velocity centrifugation. Splenic T-lymphocytes were stimulated with Dexs-Ub-HBcAg and the specific T-cell-mediated immune responses were examined. Cytokine expression was analyzed using enzyme-linked immunosorbent assays. T-lymphocyte proliferation was detected using a Cell Counting Kit-8 assay and HBcAg-specific CTL activity was determined using a lactate dehydrogenase release assay. The results revealed that Dexs-Ub-HBcAg effectively stimulated T-cell proliferation and induced the activation of antigen-specific CTLs to exhibit HBcAg-specific CTL immune responses in vitro. These results suggest the potential of Dexs-Ub-HBcAg for development as a future therapeutic option for the elimination of HBV.

Current Challenges and Future Perspectives of Diagnosis of Hepatitis B Virus.

It is estimated that approximately 260 million people worldwide are infected with the hepatitis B virus (HBV), which is one of the leading causes of liver disease and liver cancer throughout the world. Compared with developed countries, low-income and middle-income countries have limited access to resources and advanced technologies that require highly specialized staff for HBV diagnosis. In spite of the heavy burden caused by hepatitis B virus, 90% of people are still undiagnosed. The World Health Organization (WHO) goal of eliminating hepatitis B by 2030 seems very difficult to achieve due to the existing diagnostic infrastructure in low-resource regions. The majority of diagnostic laboratories still use hepatitis B surface antigen (HBsAg)-based tests. WHO's elimination plan is at risk of derailment due to phases like the window period, immune control, and occult HBV infection (OBI) not being detected by standard tests. Here, in this article, we are focusing on various diagnostic platforms for the better diagnosis of HBV. The aim of the elimination of HBV can only be achieved by detecting all phases of HBV infection, which can be executed by a combined approach of using new marker assays along with advanced pretesting and testing methods.

CRISPR/Cas9 delivery by NIR-responsive biomimetic nanoparticles for targeted HBV therapy

BackgroundCurrently, there are no curative drugs for hepatitis B virus (HBV). Complete elimination of HBV covalently closed circular DNA (cccDNA) is key to the complete cure of hepatitis B virus infection. The CRISPR/Cas9 system can directly destroy HBV cccDNA. However, a CRISPR/Cas9 delivery system with low immunogenicity and high efficiency has not yet been established. Moreover, effective implementation of precise remote spatiotemporal operations in CRISPR/Cas9 is a major limitation.ResultsIn this work, we designed NIR-responsive biomimetic nanoparticles (UCNPs-Cas9@CM), which could effectively deliver Cas9 RNP to achieve effective genome editing for HBV therapy. HBsAg, HBeAg, HBV pgRNA and HBV DNA along with cccDNA in HBV-infected cells were found to be inhibited. These findings were confirmed in HBV-Tg mice, which did not exhibit significant cytotoxicity and minimal off-target DNA damage.ConclusionsThe UCNPs-based biomimetic nanoplatforms achieved the inhibition of HBV replication via CRISPR therapy and it is a potential system for efficient treatment of human HBV diseases.Graphical

Cytokines profile in patients with acute and chronic hepatitis B infection.

Hepatitis B virus (HBV) is one of the leading causes of acute and chronic hepatitis and represents a serious public health threat. Cytokines are important chemical mediators that regulate the differentiation, proliferation, and function of immune cells, with accumulating evidence indicating that the inadequate immune responses are responsible for the elimination or persistence of HBV. This study aimed to determine the cytokine profiles (IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, and IL-17A) during HBV infection and investigate their association with genotypes. A total of 66 plasma samples, 19 from patients with acute and 47 with chronic hepatitis B infection, were subjected to biochemical tests, nested-PCR, and real-time PCR, with cytokines evaluated using a commercial BD Cytometric Bead Array Human Th1/Th2/Th17 Cytokine Kit. Healthy controls (10 individuals) were selected from blood donors with no history of liver diseases. No correlation was found between genotypes, viral load, and cytokines analyzed. All cytokines showed higher levels of production among infected individuals when compared with the control group. A positive correlation classified as moderate to strong was found between cytokines IFN-γ, TNF, IL-10, IL-6, IL-4, and IL-2 through the Spearman correlation coefficient. TNF (P = 0.009), IL-10 (P < 0.001), and IL-6 (P < 0.001) levels were higher in acute individuals compared with chronic and control groups. Theses cytokines could be involved in the elimination of virus and protection against chronicity.

The Clinical Significance and Mechanism of the Effect for Hepatitis B Virus Protein on Host Immune

The cytotoxic effect targeting hepatitis B virus (HBV) infected hepatocytes from virus-specific cytotoxic T cells and the neutralizing antibodies secreted by virus-specific B cells play an important role in the immune control and elimination of HBV. In patients with chronic hepatitis B, the liver immune microenvironment usually presents a suppression state, and virus-specific immune cells are mostly exhausted. Studies on the interaction between HBV and host immunity during infection, especially the influence of various viral proteins on immune cell function, will contribute to understanding the mechanism of the chronicity of HBV infection, disease progression, and optimization of immunotherapy against HBV. The review summarized the suppressive effects of HBV viral proteins on the host innate immunity and adaptive immune system, to help us understanding the mechanism(s) relevant to the observation that a CHB patient with HBeAg loss and lower HBsAg level is more likley achieving functionall cure. and expect to provide new sights for accelerate virus clearance and achieve functional cure of chronic hepatitis B, by removing the HBV viral proteins and consequently, liberting host immune from suppression state.

Toward a new era of hepatitis B virus therapeutics: The pursuit of a functional cure.

Hepatitis B virus (HBV) infection, although preventable by vaccination, remains a global health problem and a major cause of chronic liver disease. Although current treatment strategies suppress viral replication very efficiently, the optimal endpoint of hepatitis B surface antigen (HBsAg) clearance is rarely achieved. Moreover, the thorny problems of persistent chromatin-like covalently closed circular DNA and the presence of integrated HBV DNA in the host genome are ignored. Therefore, the scientific community has focused on developing innovative therapeutic approaches to achieve a functional cure of HBV, defined as undetectable HBV DNA and HBsAg loss over a limited treatment period. A deeper understanding of the HBV life cycle has led to the introduction of novel direct-acting antivirals that exert their function through multiple mechanisms, including inhibition of viral entry, transcriptional silencing, epigenetic manipulation, interference with capsid assembly, and disruption of HBsAg release. In parallel, another category of new drugs aims to restore dysregulated immune function in chronic hepatitis B accompanied by lethargic cellular and humoral responses. Stimulation of innate immunity by pattern-recognition receptor agonists leads to upregulation of antiviral cytokine expression and appears to contribute to HBV containment. Immune checkpoint inhibitors and adoptive transfer of genetically engineered T cells are breakthrough technologies currently being explored that may elicit potent HBV-specific T-cell responses. In addition, several clinical trials are attempting to clarify the role of therapeutic vaccination in this setting. Ultimately, it is increasingly recognized that elimination of HBV requires a treatment regimen based on a combination of multiple drugs. This review describes the rationale for progressive therapeutic interventions and discusses the latest findings in the field of HBV therapeutics.

Impact of Coronavirus Disease 2019 Pandemic on Viral Hepatitis Elimination: What Is the Price?

In 2016, the World Health Organization developed a plan for viral hepatitis elimination by 2030. Globally, control of hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most challenging aspects of viral hepatitis elimination. In many developed countries elimination of HBV could be targeted to special populations mostly immigrants from low resource settings. Elimination of HCV, however, remains a challenge globally. Barriers to HCV elimination include high cost of medications and the ability to engage specific at-risk populations as well as individuals who are out of medical care. In the context of the coronavirus disease 2019 (COVID-19) pandemic, treatment access and screening have been further negatively impacted by social distancing rules and COVID-19-related anxieties. This threatens to throw most countries off course in their elimination efforts. Before the pandemic, some states in the United States had scaled up their elimination efforts with plans to ramp up testing and treatment using Netflix-like payment models for HCV direct acting antiviral drugs. Most of these efforts have stalled on account of the health system's focus on COVID-19 control. To prevent further delays in achieving elimination targets, programs would need to explore new models of care that address COVID-19-related access hurdles. Systems that leverage technologies such as telemedicine and self-testing could help maintain treatment levels. Mathematical models estimate that COVID-19-related delays in 2020 could lead to 44,800 hepatocellular cancers and 72,300 liver-related deaths for the next decade.

Novel vector preS1-tp fusion protein effectively inhibits hepatitis B virus replication and cccDNA synthesis by mediating hepatitis B virus targeting sequence small interfering RNA

Objective: To study the use of preS1-tp fusion protein as a novel vector to mediate the entry of small interfering RNA (siRNA) targeting the carboxy-terminal nuclear localization signal (NLS) region of hepatitis B virus (HBV) core protein into HBV-infected hepatocytes, and to further explore the HBV replication inhibition and covalently closed circular DNA synthesis. Methods: HepG2.2.15 cells expressing the human sodium taurocholate co-transporting polypeptide were established on the basis of lentivirus infection system. siRNA against HBV NLS region was designed and synthesized. PreS1-tp fusion protein expression and purification was observed to test its ability to cell entry and DNA binding. NLS siRNA were delivered into HepG2.2.15- sodium taurocholate co-transporting polypeptide cells by preS1-tp fusion protein as a vector to observe the effects of NLS siRNA on HBV replication and covalently closed circular DNA levels. Analysis of variance was used for comparison between multiple groups, and the measurement data differences between groups were analyzed by t-test. Results: HepG2.2.15-sodium taurocholate co-transporting polypeptide cell line was successfully constructed. Screened synthetic HBV NLS siRNA had significantly inhibited HBV replication. The preS1-tp fusion protein was expressed and purified on a large-scale. The fusion protein as a vector for HBV NLS siRNA had targeted delivery. The result showed that the fusion protein had effectively targeted siRNA to Hepg2.2.15-sodium taurocholate co-transporting polypeptide cell, which not only had effectively inhibited the expression of HBV mRNA, HBsAg and HBeAg, but also had significantly reduced the levels of HBV DNA and covalently closed circular DNA. Conclusion: The preS1-tp fusion protein constructed in this study uses the dual functional characteristics of preS1 binding to hepatocyte HBV receptor, and tp binding to nucleic acids, and targets HBV NLS siRNA against HBV-infected cells and block rcDNA from being transported to nucleus. siRNA plays a role in inhibiting HBV replication and covalently close circular DNA synthesis, providing a new strategy for the treatment of chronic hepatitis B caused by HBV infection, and a new research perspective for the complete elimination of HBV from the body.

Liver-Resident Memory CD8+ T Cells: Possible Roles in Chronic HBV Infection.

Achieving a functional cure for chronic hepatitis B virus (HBV) infection or complete elimination of HBV covalently closed circular DNA (cccDNA) has been challenging in the treatment of patients with chronic HBV infection. Although novel antivirals are being investigated, improving HBV-specific adaptive immune responses is also important for durable viral clearance. Tissue-resident memory CD8+ T (TRM) cells were recently reported as a T-cell population that resides in peripheral tissues and does not recirculate. TRM cells have been studied in the livers of mice and humans. Liver TRM cells have distinct characteristics compared to T cells in peripheral blood or other tissues, which may be associated with the unique microenvironment of the liver. In this review, we describe the characteristics of liver TRM cells and their implications in chronic HBV infection. We emphasize that liver TRM cells can be an immunotherapeutic target for the treatment of chronic HBV infection.

Elimination of Hepatitis B in Highly Endemic Settings: Lessons Learned in Taiwan and Challenges Ahead.

Hepatitis B virus (HBV) infection and its related liver diseases are important health problems worldwide, particularly in the Asia-Pacific region. For the past 4–5 decades, Taiwan’s government and scientists have cooperated together to control this virus infection and its related liver diseases. These efforts and achievements have made progress toward the elimination of HBV. Taiwan’s government initiated the Viral Hepatitis Control Program (VHCP) in the1970s, and then launched the national vaccination program in 1984. This universal vaccination program effectively decreased the rate of hepatitis B carriage and the development of hepatocellular carcinoma (HCC) in the younger generation. Since 2003, approved anti-HBV treatments were reimbursed nationwide. This reimbursement program resulted in a higher uptake of anti-HBV treatments, which contributed to a decrease in liver-related disease progression and subsequently reduced attributable mortality in Taiwan. This experience can be shared by countries in other parts of the world regarding the control of chronic viral hepatitis B.

Mathematical Modeling for Hepatitis B Virus: Would Spatial Effects Play a Role and How to Model It?

For nearly 250 million people worldwide suffering from chronic hepatitis B virus (HBV) infection, there are few effective options for treatment (Schweitzer et al., 2015). Elimination of HBV from liver tissue remains an elusive goal; chronic HBV is exceptionally difficult to treat. It results mainly from maternal-neonatal vertical infection but also in roughly 5% of horizontal infections (Rehermann, 2013), and is characterized by the entrenchment of viral covalently closed circular DNA (cccDNA) in host nuclei. cccDNA persistence and HBV resurgence under multiple scenarios [e.g., immunosuppression for chemotherapy (Hoofnagle, 2009)] are associated with liver pathologies such as tissue damage (fibrosis, cirrhosis) and hepatic carcinomas (Ikeda et al., 2010). Current treatments are aimed at mitigating such long-term pathological effects and require sustained and prolonged protocols, yet do not eradicate cccDNA leading to reactivation upon cessation (Guo and Guo, 2015). cccDNA entrenchment further evades detection—with some occult DNA levels well under 100 copies/ml—complicating transfusions or transplantations (Schmeltzer and Sherman, 2010). Efforts at mimicking and exploiting the successful immune response in the 95% of acute horizontal infections requires delineating precisely how the immune systems interact with HBV, and we do not have a clear characterization of the HBV-immune dynamic (Guidotti et al., 2015; Seeger and Mason, 2015). The two levels of infectious response, (i) the innate and (ii) the adaptive, recognize and respond in distinct ways to HBV challenges while modulating each other. Their success or failure influences whether the HBV challenges are resolved with an acute infection and immunity, or a chronic condition with numerous collateral complications (Rehermann, 2013). Innate immune activity, as with the natural killer (NK) cells and resident liver macrophages, or the Kupffer cells, and its more generalized recognition of pathogens are proposed either essentially blind to a “stealth” infection of HBV (Chang and Guo, 2015), or are a critical and “exquisite” guardian against successful HBV colonization (Guidotti et al., 2015). Meanwhile, adaptive responses (e.g., CD4+/CD8+ T-Cells) and their specific targeting of HBV are proposed essential for restricting infection to the transient acute while buttressing immunity against future challenges (Chisari et al., 2010). Evaluating novel treatments is further complicated by observations of evidently disruptive interactions between innate and adaptive immune activity. Uptake mechanisms observed key to HBV invasion, the sodium-taurocholate co-transporting polypeptide or NTCP (Watashi et al., 2014), is a promising target for blocking HBV uptake. However, innate release of interleukin-6 (IL-6) that interferes with HBV replication and downregulates NTCP also blocks apoptotic mechanisms and may even assist HBV progress (Hosel et al., 2009). The HBV cccDNA itself is a natural prime target, and in vitro studies with HepaRG cell lines that show interferon-alpha and lymphotoxin-beta stimulus without cytolytic behavior appears promising (Lucifora et al., 2014), but must be advanced with caution. Innate NK cells were observed to perform unexpected termination of adaptive CD8+ T-cells when pharmacologically stimulated to produce interferon family cytokines (Guidotti et al., 2015). Additionally, dependence of chronic or acute manifestations on the sheer number of HBV suggests an optimal invasion population strategy for HBV (Asabe et al., 2009), presumably evading detection but sufficient for colonization. Unfortunately, direct study of the initial HBV-immune dynamic in patients is difficult or simply not possible, hence the attention given to animal and mathematical models (Murray and Goyal, 2015; Cangelosi et al., 2017).

Molecular signature of hepatitisB virus regulation by interferon-γ in primary human hepatocytes.

A complete cure for chronic hepatitisB virus (HBV) infection requires elimination of covalently closed circular DNA; however, this remains to be clinically achieved. Interferon (IFN)-γ, a typeII IFN, is produced by intrahepatic cytotoxic Tlymphocytes and has non-cytolytic antiviral potential. However, the mechanism by which IFN-γ regulates HBV infection has not been fully elucidated. Thus, we developed an invitro HBV infection assay system and analyzed the molecular signature of HBV regulation by IFN-γ. The invitro HBV infection assay system was established in primary human hepatocytes infected with HBV derived from the plasmid containing 1.3-mer HBV genome, and treated with IFN-γ. The antiviral effects and signaling pathways of IFN-γ were examined using microarray, and assessed by siRNA knockdown experiments of the related genes. IFN-γ treatment suppressed both HBV propagation and transcription as efficiently as IFN-α. Microarray analysis showed that IFN-γ stimulation induced the activation of both IFN-γ and IFN-α signaling, regulating HBV covalently closed circular DNA. HBV production was decreased by IFN-γ through Janus kinase/signal transducer and activator of transcription signaling and interferon-stimulated genes, such as 2'-5'-oligoadenylate synthase2 and apolipoproteinB mRNA editing enzyme catalytic subunit3G. IFN-γ can suppress HBV propagation and transcription in hepatocytes by activating specific intracellular signaling pathways in hepatocytes, and suggests the future application of these particular signaling pathways or genes for the complete elimination of HBV.