HBV and the immune response Ferrari, Carlo
Liver international,
January 2015, Volume:
35, Issue:
s1
Journal Article
Peer reviewed
Hepatitis B virus (HBV) infection acquired in adult life is generally self‐limited while chronic persistence of the virus is the prevalent outcome when infection is acquired perinatally. Both control ...of infection and liver cell injury are strictly dependent upon protective immune responses, because hepatocyte damage is the price that the host must pay to get rid of intracellular virus. Resolution of acute hepatitis B is associated with functionally efficient, multispecific antiviral T‐cell responses which are preceded by a poor induction of intracellular innate responses at the early stages of infection. Persistent control of infection is provided by long‐lasting protective memory, which is probably sustained by continuous stimulation of the immune system by trace amounts of virus which are never totally eliminated, persisting in an occult episomic form in the nucleus of liver cells even after recovery from acute infection. Chronic virus persistence is instead characterized by a lack of protective T‐cell memory maturation and by an exhaustion of HBV‐specific T‐cell responses. Persistent exposure of T cells to high antigen loads is a key determinant of functional T‐cell impairment but also other mechanisms can contribute to T‐cell inhibition, including the tolerogenic effect of the liver environment. The degree of T‐cell impairment is variable and its severity is related to the level of virus replication and antigen load. The antiviral T‐cell function is more efficient in patients who can control infection either partially, such as inactive HBsAg carriers with low levels of virus replication, or completely, such as patients who achieve HBsAg loss either spontaneously or after antiviral therapy. Thus, understanding the features of the immune responses associated with control of infection is needed for the successful design of novel immune modulatory therapies based on the reconstitution of efficient antiviral responses in chronic HBV patients.
Knowledge of the immunological events necessary to control hepatitis B virus (HBV) infection has accelerated in recent years, but their translation towards therapeutic strategies able to achieve a ...durable HBV suppression has been challenging. The scenario of how HBV deals with the host immunity is presented and used to discuss how the immune response can be harnessed to potentially achieve infection control.
Sulla strada del ritorno da Roma dopo l’incoronazione imperiale, Carlo Magno ordinò che la statua equestre in bronzo collocata davanti al palatium di Ravenna e raffigurante il re ariano Teoderico ...fosse trasferita ad Aquisgrana – una scelta che è sembrata a molti difficilmente compatibile con il ruolo di sovrano cattolico e difensore della Chiesa di Carlo, e che è stata spesso spiegata facendo riferimento quasi esclusivamente alle qualità artistiche del monumento. Tuttavia, le ragioni che spinsero il nuovo imperatore a un gesto così sorprendente furono essenzialmente politiche e riconducibili in primis ai molti significati che il monumento equestre di Teoderico permetteva di esprimere. Trasferendo ad Aquisgrana l’effigie del grande re ostrogoto, Carlo Magno volle pertanto mostrare – dentro e fuori i suoi domini – in che modo egli intendesse la sua nuova dignità imperiale.
The correct determination of protein-protein interaction interfaces is important for understanding disease mechanisms and for rational drug design. To date, several computational methods for the ...prediction of protein interfaces have been developed, but the interface prediction problem is still not fully understood. Experimental evidence suggests that the location of binding sites is imprinted in the protein structure, but there are major differences among the interfaces of the various protein types: the characterising properties can vary a lot depending on the interaction type and function. The selection of an optimal set of features characterising the protein interface and the development of an effective method to represent and capture the complex protein recognition patterns are of paramount importance for this task.
In this work we investigate the potential of a novel local surface descriptor based on 3D Zernike moments for the interface prediction task. Descriptors invariant to roto-translations are extracted from circular patches of the protein surface enriched with physico-chemical properties from the HQI8 amino acid index set, and are used as samples for a binary classification problem. Support Vector Machines are used as a classifier to distinguish interface local surface patches from non-interface ones. The proposed method was validated on 16 classes of proteins extracted from the Protein-Protein Docking Benchmark 5.0 and compared to other state-of-the-art protein interface predictors (SPPIDER, PrISE and NPS-HomPPI).
The 3D Zernike descriptors are able to capture the similarity among patterns of physico-chemical and biochemical properties mapped on the protein surface arising from the various spatial arrangements of the underlying residues, and their usage can be easily extended to other sets of amino acid properties. The results suggest that the choice of a proper set of features characterising the protein interface is crucial for the interface prediction task, and that optimality strongly depends on the class of proteins whose interface we want to characterise. We postulate that different protein classes should be treated separately and that it is necessary to identify an optimal set of features for each protein class.
Protein-protein interactions have pivotal roles in life processes, and aberrant interactions are associated with various disorders. Interaction site identification is key for understanding disease ...mechanisms and design new drugs. Effective and efficient computational methods for the PPI prediction are of great value due to the overall cost of experimental methods. Promising results have been obtained using machine learning methods and deep learning techniques, but their effectiveness depends on protein representation and feature selection.
We define a new abstraction of the protein structure, called hierarchical representations, considering and quantifying spatial and sequential neighboring among amino acids. We also investigate the effect of molecular abstractions using the Graph Convolutional Networks technique to classify amino acids as interface and no-interface ones. Our study takes into account three abstractions, hierarchical representations, contact map, and the residue sequence, and considers the eight functional classes of proteins extracted from the Protein-Protein Docking Benchmark 5.0. The performance of our method, evaluated using standard metrics, is compared to the ones obtained with some state-of-the-art protein interface predictors. The analysis of the performance values shows that our method outperforms the considered competitors when the considered molecules are structurally similar.
The hierarchical representation can capture the structural properties that promote the interactions and can be used to represent proteins with unknown structures by codifying only their sequential neighboring. Analyzing the results, we conclude that classes should be arranged according to their architectures rather than functions.
Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV treatment endpoints to guide ...clinical trials aiming to ‘cure’ HBV. Agreement among the conference participants was reached on some key points. ‘Functional’ but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive or negative chronic hepatitis, who are treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV ‘functional cure’, the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.
In this work we study a Susceptible-Infected-Susceptible model coupled with a continuous opinion dynamics model. We assume that each individual can take measures to reduce the probability of ...contagion, and the level of effort each agent applies can change due to social interactions. We propose simple rules to model the propagation of behaviors that modify the level of effort, and analyze their impact on the dynamics of the disease. We derive a two dimensional set of ordinary differential equations describing the dynamic of the proportion of the number of infected individuals and the mean value of the effort parameter, and analyze the equilibria of the system. The stability of the endemic phase and disease free equilibria depends only on the mean value of the levels of efforts, and not on the initial distribution of levels of effort.
A great effort of research has been devoted in the last few years to developing new anti-HBV therapies of finite duration that also provide effective sustained control of virus replication and ...antigen production. Among the potential therapeutic strategies, immune-modulation represents a promising option to cure HBV infection and the adaptive immune response is a rational target for novel therapeutic interventions, in consideration of the key role played by T cells in the control of virus infections. HBV-specific T cells are severely dysfunctional in chronic HBV infection as a result of several inhibitory mechanisms which are simultaneously active within the chronically inflamed liver. Indeed, the liver is a tolerogenic organ harboring different non-parenchymal cell populations which can serve as antigen presenting cells (APC) but are poorly efficient in effector T cell priming, with propensity to induce T cell tolerance rather than T cell activation, because of a poor expression of co-stimulatory molecules, up-regulation of the co-inhibitory ligands PD-L1 and PD-L2 upon IFN stimulation, and production of immune regulatory cytokines, such as IL10 and TGF-β. They include resident dendritic cells (DCs), comprising myeloid and plasmacytoid DCs, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatic stellate cells (HSCs) as well as the hepatocytes themselves. Additional regulatory mechanisms which contribute to T cell attrition in the chronically infected liver are the high levels of soluble mediators, such as arginase, indoleamine 2,3-dioxygenase (IDO) and suppressive cytokines, the up-regulation of inhibitory checkpoint receptor/ligand pairs, the expansion of regulatory cells, such as CD4+FOXp3+ Treg cells, myeloid-derived suppressor cells and NK cells. This review will deal with the interactions between immune cells and liver environment discussing the different mechanisms which contribute to T cell dysfunction in chronic hepatitis B, some of which are specifically activated in HBV infection and others which are instead common to chronic inflammatory liver diseases in general. Therapeutic interventions targeting dysregulated pathways and cellular functions will be also delineated.
Adaptive immunity in HBV infection Bertoletti, Antonio; Ferrari, Carlo
Journal of hepatology,
04/2016, Volume:
64, Issue:
1
Journal Article
Peer reviewed
Summary During hepatitis B virus (HBV) infection, the presence of HBV-specific antibody producing B cells and functional HBV-specific T cells (with helper or cytotoxic effects) ultimately determines ...HBV infection outcome. In this review, in addition to summarizing the present state of knowledge of HBV-adaptive immunity, we will highlight controversies and uncertainties concerning the HBV-specific B and T lymphocyte response, and propose future directions for research aimed at the generation of more efficient immunotherapeutic strategies.
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