Toward a complete cure for chronic hepatitis B: Novel therapeutic targets for hepatitis B virus.
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ABSTRACT:
SUBMITTER: Kim SW
PROVIDER: S-EPMC8755466 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chronic infection with HBV is a major cause of advanced liver disease and hepatocellular carcinoma. Nucleos(t)ide analogues effectively control HBV replication but viral cure is rare. Hence treatment has often to be administered for an indefinite duration, increasing the risk for selection of drug resistant virus variants. PEG-interferon-α-based therapies can sometimes cure infection but suffer from a low response rate and severe side-effects. CHB is characterized by the persistence of a nuclear covalently closed circular DNA (cccDNA), which is not targeted by approved drugs. Targeting host factors which contribute to the viral life cycle provides new opportunities for the development of innovative therapeutic strategies aiming at HBV cure. An improved understanding of the host immune system has resulted in new potentially curative candidate approaches. Here, we review the recent advances in understanding HBV-host interactions and highlight how this knowledge contributes to exploiting host-targeting strategies for a viral cure.
| S-EPMC7613419 | biostudies-literature
Project description: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.
| S-EPMC8173382 | biostudies-literature
Project description:IntroductionHepatitis E virus (HEV) is one of the most common causes of acute viral hepatitis in the world with an estimated 20 million infections per year. Although the mortality rate is < 1% among the general population, pregnant women can have a fatality rate of up to 30%. Additionally, chronic hepatitis E has increasingly become a significant clinical problem in immunocompromised individuals. Effective antivirals against HEV are needed.Areas coveredThis review article addresses the current state of knowledge of HEV infections with regard to animal and cell culture model systems that are important for antiviral discovery and testing, our current understanding of the molecular mechanisms of virus replication, our understanding of how each viral protein functions, and areas that can potentially be exploited as therapeutic targets.Expert opinionLack of an efficient cell culture system for HEV propagation, the limited knowledge of HEV lifecycle, and the inherent self-limiting infection within the normal populace make the development of new therapeutic agents against HEV challenging. There are many promising therapeutic targets, and the tools for identifying and testing potential antivirals are rapidly evolving. The development of effective therapeutics against HEV in immunocompromised and pregnant patient populations is warranted.
| S-EPMC4834873 | biostudies-literature
Project description:Recently, small-molecule covalent inhibitors have been accepted as a practical tool for targeting previously "undruggable" proteins. The high target selectivity of modern covalent inhibitors is now alleviating toxicity concerns regarding the covalent modifications of proteins. However, despite the tremendous clinical success of current covalent inhibitors, there are still unmet medical needs that covalent inhibitors have not yet addressed. This review categorized representative covalent inhibitors based on their mechanism of covalent inhibition: conventional covalent inhibitors, targeted covalent inhibitors (TCIs), and expanded TCIs. By reviewing both Food and Drug Administration (FDA)-approved drugs and drug candidates from recent literature, we provide insight into the future direction of covalent inhibitor development.
| S-EPMC9786830 | biostudies-literature
Project description:Hepatitis B virus (HBV) is a hepadnavirus, a small DNA virus that infects liver tissue, with some unusual replication steps that share similarities to retroviruses. HBV infection can lead to chronic hepatitis B (CHB), a life-long infection associated with significant risks of liver disease, especially if untreated. HBV is a significant global health problem, with hundreds of millions currently living with CHB. Currently approved strategies to prevent or inhibit HBV are highly effective, however, a cure for CHB has remained elusive. To achieve a cure, elimination of the functionally integrated HBV covalently closed chromosomal DNA (cccDNA) genome is required. The capsid core is an essential component of HBV replication, serving roles when establishing infection and in creating new virions. Over the last two and a half decades, significant efforts have been made to find and characterize antivirals that target the capsid, specifically the HBV core protein (Cp). The antivirals that interfere with the kinetics and morphology of the capsid, termed capsid assembly modulators (CAMs), are extremely potent, and clinical investigations indicate they are well tolerated and highly effective. Several CAMs offer the potential to cure CHB by decreasing the cccDNA pools. Here, we review the biology of the HBV capsid, focused on Cp, and the development of inhibitors that target it.
| S-EPMC10461335 | biostudies-literature
Project description:Purpose of reviewChronic hepatitis B (CHB), caused by hepatitis B virus (HBV), is a major cause of advanced liver disease and hepatocellular carcinoma (HCC) worldwide. HBV replication is characterized by the synthesis of covalently closed circular (ccc) DNA which is not targeted by antiviral nucleos(t)ide analogues (NUCs) the key modality of standard of care. While HBV replication is successfully suppressed in treated patients, they remain at risk for developing HCC. While functional cure, characterized by loss of HBsAg, is the first goal of novel antiviral therapies, curative treatments eliminating cccDNA remain the ultimate goal. This review summarizes recent advances in the discovery and development of novel therapeutic strategies and their impact on cccDNA biology.Recent findingsWithin the last decade, substantial progress has been made in the understanding of cccDNA biology including the discovery of host dependency factors, epigenetic regulation of cccDNA transcription and immune-mediated degradation. Several approaches targeting cccDNA either in a direct or indirect manner are currently at the stage of discovery, preclinical or early clinical development. Examples include genome-editing approaches, strategies targeting host dependency factors or epigenetic gene regulation, nucleocapsid modulators and immune-mediated degradation.SummaryWhile direct-targeting cccDNA strategies are still largely at the preclinical stage of development, capsid assembly modulators and immune-based approaches have reached the clinical phase. Clinical trials are ongoing to assess their efficacy and safety in patients including their impact on viral cccDNA. Combination therapies provide additional opportunities to overcome current limitations of individual approaches.
| S-EPMC7613435 | biostudies-literature
Project description:"Functional cure" is being pursued as the ultimate endpoint of antiviral treatment in chronic hepatitis B (CHB), which is characterized by loss of HBsAg whether or not anti-HBs antibodies are present. "Functional cure" can be achieved in <10% of CHB patients with currently available therapeutic agents. The dysfunction of specific immune responses to hepatitis B virus (HBV) is considered the major cause of persistent HBV infection. Thus, modulating the host immune system to strengthen specific cellular immune reactions might help eliminate HBV. Strategies are needed to restore/enhance innate immunity and induce HBV-specific adaptive immune responses in a coordinated way. Immune and resident cells express pattern recognition receptors like TLRs and RIG I/MDA5, which play important roles in the induction of innate immunity through sensing of pathogen-associated molecular patterns (PAMPs) and bridging to adaptive immunity for pathogen-specific immune control. TLR/RIG I agonists activate innate immune responses and suppress HBV replication in vitro and in vivo, and are being investigated in clinical trials. On the other hand, HBV-specific immune responses could be induced by therapeutic vaccines, including protein (HBsAg/preS and HBcAg), DNA, and viral vector-based vaccines. More than 50 clinical trials have been performed to assess therapeutic vaccines in CHB treatment, some of which display potential effects. Most recently, using genetic editing technology to generate CAR-T or TCR-T, HBV-specific T cells have been produced to efficiently clear HBV. This review summarizes the progress in basic and clinical research investigating immunomodulatory strategies for curing chronic HBV infection, and critically discusses the rather disappointing results of current clinical trials and future strategies.
| S-EPMC7018702 | biostudies-literature
Project description:BACKGROUND:Chronic Hepatitis B (CHB) remains a major problem for global public health. Viral persistence and immune defects are the two major reasons for CHB, and it was hypothesized that based on a transient clearance of serum viral DNA and HBsAg "window stage", active immunization against hepatitis B virus (HBV) might initiate effective host immune responses versus HBV to achieve functional cure of CHB. METHODS:Two experimental mouse models that mice hydrodynamic injected HBV DNA or infected with recombinant AAV/HBV were used. The "sandwich" therapeutic effect by using a potent human anti-HBsAg neutralizing monoclonal antibody (G12) in combination with antiviral drug tenofovir disoproxil fumarate (TDF), followed by active immunization with HBsAg-HBsAb (mYIC) was evaluated. FINDINGS:A single G12 injection rapidly cleared serum HBsAg in HDI-HBV carrier mice, with a synergistic effect in decreasing viral DNA load when TDF was given orally. When both serum viral DNA and HBsAg load became low or undetectable, mYIC was administered. A more effective clearance of viral DNA and HBsAg was observed and serum HBsAb was developed only in these "sandwich"-treated mice. Efficient intrahepatic anti-HBV immune responses were also observed in these mice, including the formation of aggregates of myeloid cells with CD8+T cells and increased TNF-α, granzyme B production. INTERPRETATION:The "sandwich" combination therapy not only efficiently decreased HBsAg and HBV DNA levels but also induced effective cellular and humoral immunity, which may result in functional cure of CHB.
| S-EPMC6945269 | biostudies-literature
Project description:More than 500,000 people die each year from the liver diseases that result from chronic hepatitis B virus (HBV) infection. Therapeutic vaccines, which aim to elicit an immune response capable of controlling the virus, offer a potential new treatment strategy for chronic hepatitis B. Recently, an evolved, high-titer vaccine platform consisting of Semliki Forest virus RNA replicons that express the vesicular stomatitis virus glycoprotein (VSV G) has been described. This platform generates virus-like vesicles (VLVs) that contain VSV G but no other viral structural proteins. We report here that the evolved VLV vector engineered to additionally express the HBV middle surface envelope glycoprotein (MHBs) induces functional CD8 T cell responses in mice. These responses were greater in magnitude and broader in specificity than those obtained with other immunization strategies, including recombinant protein and DNA. Additionally, a single immunization with VLV-MHBs protected mice from HBV hydrodynamic challenge, and this protection correlated with the elicitation of a CD8 T cell recall response. In contrast to MHBs, a VLV expressing HBV core protein (HBcAg) neither induced a CD8 T cell response in mice nor protected against challenge. Finally, combining DNA and VLV-MHBs immunization led to induction of HBV-specific CD8 T cell responses in a transgenic mouse model of chronic HBV infection. The ability of VLV-MHBs to induce a multispecific T cell response capable of controlling HBV replication, and to generate immune responses in a tolerogenic model of chronic infection, indicates that VLV vaccine platforms may offer a unique strategy for HBV therapeutic vaccination.HBV infection is associated with significant morbidity and mortality. Furthermore, treatments for chronic infection are suboptimal and rarely result in complete elimination of the virus. Therapeutic vaccines represent a unique approach to HBV treatment and have the potential to induce long-term control of infection. Recently, a virus-based vector system that combines the nonstructural proteins of Semliki Forest virus with the VSV glycoprotein has been described. In this study, we used this system to construct a novel HBV vaccine and demonstrated that the vaccine is capable of inducing virus-specific immune responses in mouse models of acute and chronic HBV replication. These findings highlight the potential of this new vaccine system and support the idea that highly immunogenic vaccines, such as viral vectors, may be useful in the treatment of chronic hepatitis B.
| S-EPMC4580199 | biostudies-literature
Project description:Chronic infection with Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality worldwide. HBV-DNA integration into the human genome is recognized as a frequent event occurring during the early phases of HBV infection and characterizing the entire course of HBV natural history. The development of refined molecular biology technologies sheds new light on the functional implications of HBV-DNA integration into the human genome, including its role in the progression of HBV-related pathogenesis and in triggering the establishment of pro-oncogenic mechanisms, promoting the development of hepatocellular carcinoma. The present review provides an updated and comprehensive overview of the current body of knowledge on HBV-DNA integration, focusing on the molecular mechanisms underlying HBV-DNA integration and its occurrence throughout the different phases characterizing the natural history of HBV infection. Furthermore, here we discuss the main clinical implications of HBV integration as a biomarker of HBV-related pathogenesis, particularly in reference to hepatocarcinogenesis, and how integration may act as a barrier to the achievement of HBV cure with current and novel antiviral therapies. Overall, a more refined insight into the mechanisms and functionality of HBV integration is paramount, since it can potentially inform the design of ad hoc diagnostic tools with the ability to reveal HBV integration events perturbating relevant intracellular pathways and for identifying novel therapeutic strategies targeting alterations directly related to HBV integration.
| S-EPMC9478028 | biostudies-literature