The role of infected cell proliferation in the clearance of acute HBV Infection in humans

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Around 90–95% of hepatitis B virus (HBV) infected adults do not progress to the chronic phase and, instead, recover naturally. The strengths of the cytolytic and non-cytolytic immune responses are key players that decide the fate of acute HBV infection. In addition, it has been hypothesized that proliferation of infected cells resulting in uninfected progeny and/or cytokine-mediated degradation of covalently closed circular DNA (cccDNA) leading to the cure of infected cells are two major mechanisms assisting the adaptive immune response in the clearance of acute HBV infection in humans. We employed fitting of mathematical models to human acute infection data together with physiological constraints to investigate the role of these hypothesized mechanisms in the clearance of infection. Results suggest that cellular proliferation of infected cells resulting in two uninfected cells is required to minimize the destruction of the liver during the clearance of acute HBV infection. In contrast, we find that a cytokine-mediated cure of infected cells alone is insufficient to clear acute HBV infection. In conclusion, our modeling indicates that HBV clearance without lethal loss of liver mass is associated with the production of two uninfected cells upon proliferation of an infected cell.This work was funded by National Institutes of Health grants R01-AI116868 (RMR), R01-AI028433 (ASP) and R01-OD011095 (ASP). Portions of this work were performed under the auspices of the U.S. Department of Energy under contract DE-AC52-06NA25396.info:eu-repo/semantics/publishedVersio

A global scientific strategy to cure hepatitis B

Chronic hepatitis B virus (HBV) infection is a global public health challenge on the same scale as tuberculosis, HIV, and malaria. The International Coalition to Eliminate HBV (ICE-HBV) is a coalition of experts dedicated to accelerating the discovery of a cure for chronic hepatitis B. Following extensive consultation with more than 50 scientists from across the globe, as well as key stakeholders including people affected by HBV, we have identified gaps in our current knowledge and new strategies and tools that are required to achieve HBV cure. We believe that research must focus on the discovery of interventional strategies that will permanently reduce the number of productively infected cells or permanently silence the covalently closed circular DNA in those cells, and that will stimulate HBV-specific host immune responses which mimic spontaneous resolution of HBV infection. There is also a pressing need for the establishment of repositories of standardised HBV reagents and protocols that can be accessed by all HBV researchers throughout the world. The HBV cure research agenda outlined in this position paper will contribute markedly to the goal of eliminating HBV infection worldwide

Restoring, releasing or replacing adaptive immunity in chronic hepatitis B

Multiple new therapeutic approaches are currently being developed to achieve sustained, off-treatment suppression of HBV, a persistent hepatotropic infection that kills ~2,000 people a day. A fundamental therapeutic goal is the restoration of robust HBV-specific adaptive immune responses that are able to maintain prolonged immunosurveillance of residual infection. Here, we provide insight into key components of successful T cell and B cell responses to HBV, discussing the importance of different specificities and effector functions, local intrahepatic immunity and pathogenic potential. We focus on the parallels and interactions between T cell and B cell responses, highlighting emerging areas for future investigation. We review the potential for different immunotherapies in development to restore or release endogenous adaptive immunity by direct or indirect approaches, including limitations and risks. Finally, we consider an alternative HBV treatment strategy of replacing failed endogenous immunity with infusions of highly targeted T cells or antibodies

Non-cytolytic control of hepatitis B virus replication and the role of interleukin-12 (IL-12)

Hepatitis B is a non-cytopathic virus that causes major morbidity worldwide. Data from animal models suggest that T lymphocytes can control hepatitis B virus (HBV) replication without killing infected hepatocytes through interferon-γ (IFN-γ). Furthermore, IFN-γ production is regulated by interleukin-12 (IL-12), which not only has a direct anti-viral effect but also promotes T helper-1 type cell- mediated immune responses, which are important in the control of HBV. The aim of this thesis was to investigate non-cytolytic control of HBV in human infection, and the role of virus-specific CD4+ T-cells in the resolution of chronic HBV infection. Furthermore, the role of IL-12 in human HBV infection and the potential of combining anti-viral and immunomodulatory drugs for the treatment of chronic HBV infection was investigated. Activated peripheral blood mononuclear cells (PBMC) from chronically infected HBV carriers reduced cytoplasmic HBV DNA in a liver cell line by releasing IFN-γ, and without killing hepatocytes. Furthermore, recombinant IFN-γ reduced the levels of HBV DNA in naturally infected hepatocytes by between 0.3 to 3 log10 and the level of HBV transcription by up to 71% non-cytolytically. Adoptive transfer of HBcAg-reactive CD4+T cells in bone marrow transplant recipients resulted in an ALT flare and the subsequent resolution of chronic HBV infection through the development of anti-HBs. IL-12 receptor (IL-12R) expression was reduced in chronic HBV infection as measured by flow cytometry. This may be a cause of the Th2 immune responses seen in chronic HBV infection. IL-12R expression could be increased to normal levels by recombinant human IL-12 (rhIL-12) resulting in Th1 effector functions. Combination therapy of lamivudine and IL-12 in chronically infected HBV patients has an enhanced anti-viral effect, which is associated with induction of HBcAg-specific CD4 T-cell reactivity and increased frequency of HBcAg- specific CD4+ T-cells, which produce IFN-γ

Host-virus interactions in chronic Hepatitis B

Hepatitis B virus (HBV) is a blood-borne human pathogen of worldwide importance. It replicates in the hepatocytes in the liver and causes a disease known as Hepatitis B. Approximately 3% of the world population are chronically infected with HBV. Chronic Hepatitis B (CHB) is the number one cause of hepatocellular carcinoma in the world leading to close to 1 million deaths every year. Treatment options are limited and none of them are curative due to persistence of the viral covalently closed circular (ccc)DNA, a plasmid-like molecule which serves as the template for viral transcription and replication. New therapies are urgently needed that would decrease the global burden of HBV. A better understanding of the HBV immunobiology and host-virus interactions is critical in this regard. Due to the narrow species and tissue tropism, research in this area has been hindered by a lack of suitable experimental in vivo models of HBV infection leaving a lot of gaps in our understanding of the viral immunobiology. For example, HBV interaction with the host innate immune system has been a matter of debates for years. Although most viruses trigger various pathogen recognition receptors (PRRs) in the cells they infect leading to the induction of interferons and an antiviral state, HBV does not seem to do that. It remained controversial however, whether this is because HBV is invisible to PRRs (i.e. acting as a “stealth virus”) or because it efficiently suppresses innate immune responses very early after infection. Another example is HBV immune control. In the natural history of CHB most of the patients reach the so called HBeAg-negative chronic infections stage, when the virus is under control characterized by no or a very low viral load in the absence of noticeable immune activity that is otherwise known to control the HBV replication. In this thesis we used human liver biopsy material from a large biobank of the University Hospital Basel in order to shed light on host-virus interactions in chronic hepatitis B. We established a novel short-term ex vivo liver biopsy culture system, allowing to study innate immune activation in situ in the human liver. We successfully used this system to demonstrate that HBV does not induce innate immune responses in the human liver in CHB. Importantly, HBV did also not interfere with the experimental induction of innate responses, suggesting that it behaves like a “stealth virus” staying under the radar of the cell’s defense systems. As a follow-up to this study, we discuss the implication of these findings on the potential use of modulators of innate immunity as novel therapeutics for the treatment of chronic hepatitis B. In a separate study, we sought to get an insight on how the host controls the virus during the HBeAg-negative chronic infection (ENCI) stage. By carefully analyzing HBV replication intermediates in the liver biopsies of patients of different stages of CHB, we have discovered that HBV replication is specifically inhibited downstream of pregenomic (pg)RNA production during the ENCI stage of CHB. Our findings provide a starting point for further studies in this direction that eventually should identify the mechanism behind this inhibition and harness it for therapeutic use

HBV-Specific Adaptive Immunity

The successful control of HBV infection requires an efficient expansion of distinct elements of the adaptive immune system (B cells, helper and cytotoxic T cells) that, due to the hepatotropic nature of HBV, need to operate in the liver parenchyma. In this respect, we will discuss broad features of HBV immunity in patients with resolved or chronic HBV infection and analyze how the liver environment can directly modulate HBV-immunity

Hepatitis B virus infection and the immune response: The big questions

Clinical events and the host immune response during hepatitis B virus (HBV) infection are intricately linked. Despite decades of research, important questions concerning the immunopathogenesis of chronic HBV infection remain unanswered. For example, it is unclear which immune parameters facilitate persistence, and if HBV can be completely cleared from the human liver. Recent technological breakthroughs now allow researchers to address these seemingly basic, but essential questions surrounding HBV immunity. It will be important to better define the molecular underpinnings of immune cell function and dysfunction during chronic disease and in controlled infection, with particular focus on the liver, as little information is available on the intrahepatic compartment. In the near future, it may be possible to solve some of the controversy surrounding the immune responses to HBV, and establish the features of both the innate and adaptive arms of the immune system required to achieve sustained control of HBV infection

Three-Dimensional Cellular Automaton for Modeling the Hepatitis B Virus Infection

Hepatitis B is considered as the most common hepatic in the world and may lead to cirrhosis and liver cancer. It is caused by the hepatitis B virus, which attacks and can damage the liver. In this paper we investigate a new mathematical model to study the dynamic process of HBV infection on the liver. This model is based on a three dimensional cellular automaton, which is composed of four state variables. The model takes into account the heterogeneous feature and the spatial localization of the population studied. Furthemore, since the virus doesn’t remain only on the liver surface but penetrates into the organ, our model describes better the behavior of interactions between cells and hepatitis B virus in the liver than the previous works found in the literature, which have used only two cellular automata in their models

On existence of traveling wave of an HBV infection dynamics model: A novel approach

In this work, a hepatitis B virus infection dynamics model is proposed including the spatial dependence of viruses. The existence of traveling waves for the proposed model is established through the application of the celebrated Gersgorin theorem. The procedure followed to establish the existence of a traveling wave solution is innovative and probably the first attempt of this particular approach. The elasticity of basic reproduction number with respect to some model parameters are also shown. Furthermore, the effects of spatial diffusivity of the viruses on infection are studied, and it is noticed that due to the diffusion, viruses spread rapidly throughout the liver