Virus Immune System Research Articles

A besyian regularisation neural network approach for hepatitis B virus spread prediction and immune system therapy model

The primary aim of the article is to analyze the response of the human immune system when it encounters the hepatitis B virus. This is done using a mathematical system of differential equations. The differential equation system has six components, likely representing various aspects of the immune response or virus dynamics. A Bayesian regularization neural network has been presented in the process of training. These networks are employed to find solutions for different categories or scenarios related to hepatitis B infection. The Adams method is used to generate reference data sets. The back-propagated artificial neural network, based on Bayesian regularization, is trained and validated using the generated data. The data is divided into three sets: 90% for training and 5% each for testing and validation. The correctness and effectiveness of the proposed neural network model have been assessed using various evaluation metrics. The metrics have been used in this study are Mean Square Error (MSE), histogram errors, and regression plots. These measures provide support to the neural network to approximate the immune response to the hepatitis B virus.

A stochastic approach for co-evolution process of virus and human immune system

Infectious diseases have long been a shaping force in human history, necessitating a comprehensive understanding of their dynamics. This study introduces a co-evolution model that integrates both epidemiological and evolutionary dynamics. Utilizing a system of differential equations, the model represents the interactions among susceptible, infected, and recovered populations for both ancestral and evolved viral strains. Methodologically rigorous, the model’s existence and uniqueness have been verified, and it accommodates both deterministic and stochastic cases. A myriad of graphical techniques have been employed to elucidate the model’s dynamics. Beyond its theoretical contributions, this model serves as a critical instrument for public health strategy, particularly predicting future outbreaks in scenarios where viral mutations compromise existing interventions.

Research progress on novel antiviral therapeutic drugs for chronic hepatitis B

The ideal goal of hepatitis B treatment is to achieve a functional cure, and the persistent cccDNA in the liver is a barrier to functional cure. Currently, antiviral drugs represented by pegylated interferon-α and nucleos (t) ide analogues cannot eliminate cccDNA, which is difficult to achieve functional cure. With the deepening of the exploration of various mechanisms and drug targets, significant progress has been made in the research and development of several novel drugs targeting the hepatitis B virus's life cycle and immune system, offering hope for a functional cure. This article presents an overview of the new progress in clinical research on antiviral therapy for chronic hepatitis B based on the literature published in recent years and international conference materials.

Impact of Micropolymorphism Outside the Peptide Binding Groove in the Clinically Relevant Allele HLA-C*14 on T Cell Responses in HIV-1 Infection.

ABSTRACTThere is increasing evidence for the importance of human leukocyte antigen C (HLA-C)-restricted CD8+ T cells in HIV-1 control, but these responses are relatively poorly investigated. The number of HLA-C-restricted HIV-1 epitopes identified is much smaller than those of HLA-A-restricted or HLA-B-restricted ones. Here, we utilized a mass spectrometry-based approach to identify HIV-1 peptides presented by HLA-C*14:03 protective and HLA-C*14:02 nonprotective alleles. We identified 25 8- to 11-mer HLA-I-bound HIV-1 peptides from HIV-1-infected HLA-C*14:02+/14:03+ cells. Analysis of T cell responses to these peptides identified novel 6 T cell epitopes targeted in HIV-1-infected HLA-C*14:02+/14:03+ subjects. Analyses using HLA stabilization assays demonstrated that all 6 epitope peptides exhibited higher binding to and greater cell surface stabilization of HLA-C*14:02 than HLA-C*14:03. T cell response magnitudes were typically higher in HLA-C*14:02+ than HLA-C*14:03+ individuals, with responses to the Pol KM9 and Nef epitopes being significantly higher. The results show that HLA-C*14:02 can elicit stronger T cell responses to HIV-1 than HLA-C*14:03 and suggest that the single amino acid difference between these HLA-C14 subtypes at position 21, outside the peptide-binding groove, indirectly influences the stability of peptide-HLA-C*14 complexes and induction/expansion of HIV-specific T cells. Taken together with a previous finding that KIR2DL2+ NK cells recognized HLA-C*14:03+ HIV-1-infected cells more than HLA-C*14:02+ ones, the present study indicates that these HLA-C*14 subtypes differentially impact HIV-1 control by T cells and NK cells.IMPORTANCE Some human leukocyte antigen (HLA) class I alleles are associated with good clinical outcomes in HIV-1 infection and are called protective HLA alleles. Identification of T cell epitopes restricted by protective HLA alleles can give important insight into virus-immune system interactions and inform design of immune-based prophylactic/therapeutic strategies. Although epitopes restricted by many protective HLA-A/B alleles have been identified, protective HLA-C alleles are relatively understudied. Here, we identified 6 novel T cell epitopes presented by both HLA-C*14:02 (no association with protection) and HLA-C*14:03 (protective) using a mass spectrometry-based immunopeptidome profiling approach. We found that these peptides bound to and stabilized HLA-C*14:02 better than HLA-C*14:03 and observed differences in induction/expansion of epitope-specific T cell responses in HIV-infected HLA-C*14:02+ versus HLA-C*14:03+ individuals. These results enhance understanding of how the microstructural difference at position 21 between these HLA-C*14 subtypes may influence cellular immune responses involved in viral control in HIV-1 infection.

A human coronavirus OC43-derived polypeptide causes neuropathic pain.

Human coronaviruses have been recently implicated in neurological sequelae by insufficiently understood mechanisms. We here identify an amino acid sequence within the HCoV‐OC43 p65‐like protein homologous to the evolutionarily conserved motif of myelin basic protein (MBP). Because MBP‐derived peptide exposure in the sciatic nerve produces pronociceptive activity in female rodents, we examined whether a synthetic peptide derived from the homologous region of HCoV‐OC43 (OC43p) acts by molecular mimicry to promote neuropathic pain. OC43p, but not scrambled peptides, induces mechanical hypersensitivity in rats following intrasciatic injections. Transcriptome analyses of the corresponding spinal cords reveal upregulation of genes and signaling pathways with known nociception‐, immune‐, and cellular energy‐related activities. Affinity capture shows the association of OC43p with an Na+/K+‐transporting ATPase, providing a potential direct target and mechanistic insight into virus‐induced effects on energy homeostasis and the sensory neuraxis. We propose that HCoV‐OC43 polypeptides released during infection dysregulate normal nervous system functions through molecular mimicry of MBP, leading to mechanical hypersensitivity. Our findings might provide a new paradigm for virus‐induced neuropathic pain.

Putative autoimmune mechanisms for Acute Disseminated Encephalomyelitis (ADEM) and Guillain-Barré Syndrome (GBS) associated with SARS-CoV-2 infection

The novel coronavirus severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, responsible for the ongoing COVID-19 pandemic, is associated with a broad manifestation of neurological disease, including Acute Disseminated Encephalomyelitis (ADEM) and Guillain-Barré Syndrome (GBS), amongst other forms of autoimmune encephalitis, stroke, encephalopathy, delirium, and cranial neuropathies. These phenomena are not limited to human coronaviruses but are also seen in a minority of patients in response to other viral infection. There is good evidence that an autoimmune mechanism hypothesis is likely. The final pathology is probably the culmination of mixed mechanisms such as vascular and immune dysregulation as well as direct viral invasion of neurons – though there is little if any evidence of viral invasion in the literature to date. The aim of this review is to elucidate the emerging evidence about this subset of COVID-19-associated neurological disease. This unique opportunity to study the interactions between virus and host immune and central nervous system (CNS) to gain novel insights applicable to other probable autoimmune neurological disease. I have conducted a literature search as well as drawn on my own observations from the COVID-19 and encephalitis multidisciplinary meetings at Queen Square National Hospital for Neurology and Neurosurgery, London, UK.

A computational study of a stochastic fractal-fractional hepatitis B virus infection incorporating delayed immune reactions via the exponential decay.

Recently, researchers have become interested in modelling, monitoring, and treatment of hepatitis B virus infection. Understanding the various connections between pathogens, immune systems, and general liver function is crucial. In this study, we propose a higher-order stochastically modified delay differential model for the evolution of hepatitis B virus transmission involving defensive cells. Taking into account environmental stimuli and ambiguities, we presented numerical solutions of the fractal-fractional hepatitis B virus model based on the exponential decay kernel that reviewed the hepatitis B virus immune system involving cytotoxic T lymphocyte immunological mechanisms. Furthermore, qualitative aspects of the system are analyzed such as the existence-uniqueness of the non-negative solution, where the infection endures stochastically as a result of the solution evolving within the predetermined system's equilibrium state. In certain settings, infection-free can be determined, where the illness settles down tremendously with unit probability. To predict the viability of the fractal-fractional derivative outcomes, a novel numerical approach is used, resulting in several remarkable modelling results, including a change in fractional-order δ with constant fractal-dimension ϖ, δ with changing ϖ, and δ with changing both δ and ϖ. White noise concentration has a significant impact on how bacterial infections are treated.

Modeling the virus-induced tumor-specific immune response with delay in tumor virotherapy

It is urgently required to design novel cancer therapies which lead to permanent cancer eradication or cancer control. Oncolytic virotherapy is a promising cancer treatment strategy using genetically engineered viruses which can selectively infect, replicate in and kill tumor cells without harming normal cells. Due to the variable interactions between tumor cells and oncolytic viruses (OVs) as well as the accordingly immune response, the impact of tumor virotherapy on tumor control is prominent. We propose a novel mathematical modeling framework based on delay differential equation to study tumor virotherapy with mediated antitumor immunity by OVs, which incorporates complex tumor–virus–immune system interactions. We initially study the existence and local stability of equilibria, and theoretically and numerically investigate the local Hopf bifurcation from the positive equilibrium by considering the time delay as a bifurcation parameter. Further, we analyze the direction of Hopf bifurcation and the stability of bifurcating periodic solution. Main results show that the time delay can induce Hopf bifurcation and result in periodic oscillations, indicating that the delayed tumor-specific CTL response induced by OVs leads to complex dynamics and may significantly influence the development process of tumor growth. Our findings also provide insight into important aspects of the virotherapy, including the dependence of the efficacy on key factors. We find that enhancing the induction of antitumor immunity by OVs can reduce the complexity of dynamics by strengthening the stability and show considerable effects on combating tumor. Further, proper choice of OVs with relative strong ability to lyse tumor cells is beneficial to ultimately control the development process of tumor growth.

EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 1).

Simple SummaryEpstein–Barr virus (EBV) infection usually occurs early in life. The virus persists throughout the lifespan in a latent phase mainly in B lymphocytes of immunocompetent hosts. Conditions of immunosuppression of variable origins may favor the emergence of EBV-linked lymphoid proliferations. This group of disorders, having EBV as common denominator, encompasses entities ranging from indolent diseases to aggressive lymphomas. In this review, consisting of three parts, we focus on EBV-linked lymphoid proliferations which may occur in the gastrointestinal tract. Our aim is to summarize the salient clinical, pathological, molecular and therapeutic data of this group of heterogeneous entities, often showing overlapping morphologic and immunophenotypic features despite the different clinical behavior. The correct diagnosis is essential in order to adopt the adequate treatment. In this part of the review, the available data on EBV biology, EBV-positive mucocutaneous ulcer, EBV-positive diffuse large B-cell lymphoma, not otherwise specified and classic Hodgkin lymphoma are discussed.EBV is the most common persistent virus in humans. The interaction of EBV with B lymphocytes, which are considered the virus reservoir, is at the base of the life-long latent infection. Under circumstances of immunosuppression, the balance between virus and host immune system is altered and hence, EBV-associated lymphoid proliferations may originate. These disorders encompass several entities, ranging from self-limited diseases with indolent behavior to aggressive lymphomas. The virus may infect not only B-cells, but even T- and NK-cells. The occurrence of different types of lymphoid disorders depends on both the type of infected cells and the state of host immunity. EBV-driven lymphoproliferative lesions can rarely occur in the gastrointestinal tract and may be missed even by expert pathologists due to both the uncommon site of presentation and the frequent overlapping morphology and immunophenotypic features shared by different entities. The aim of this review is to provide a comprehensive overview of the current knowledge of EBV-associated lymphoproliferative disorders, arising within the gastrointestinal tract. The review is divided in three parts. In this part, the available data on EBV biology, EBV-positive mucocutaneous ulcer, EBV-positive diffuse large B-cell lymphoma, not otherwise specified and classic Hodgkin lymphoma are discussed.

Potential Antiviral Immune Response Against COVID-19: Lessons Learned from SARS-CoV.

Virus and host innate immune system interaction plays a significant role in forming the outcome of viral diseases. Host innate immunity initially recognizes the viral invasion and induces a rapid inflammatory response, and this recognition activates signaling cascades that trigger the release of antiviral mediators. This chapter aims to explore the mechanisms by which newly emerged coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activates the host immune system. Since SARS-CoV-2 shares similarities with SARS-CoV that caused the epidemic of SARS in 2003, the pathogenesis of both viruses could be at least very similar. For this, this chapter provides a synthesis of literature concerning antiviral immunity in SARS-CoV and SARS-CoV-2. It includes the presentation of epitopes linked to SARS-CoV-2 as well as the ability of SARS-CoV-2 to cause proteolytic activation and interact with angiotensin-converting enzyme 2 (ACE2) via molecular mimicry. This chapter characterizes various mechanisms that this virus may engage in escaping the host immunity, ended by a discussion of humoral immune responses against SARS-CoV-2.

Identification of Novel SARS-CoV-2 Drug Targets by Host MicroRNAs and Transcription Factors Co-regulatory Interaction Network Analysis.

Understanding the host regulatory mechanisms opposing virus infection and virulence can provide actionable insights to identify novel therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have used a network biology approach to elucidate the crucial factors involved in host responses involving host–microRNA (miRNA) interactions with host and virus genes using recently published experimentally verified protein–protein interaction data. We were able to identify 311 host genes to be potentially targetable by 2,197 human miRNAs. These miRNAs are known to be involved in various biological processes, such as T-cell differentiation and activation, virus replication, and immune system. Among these, the anti-viral activity of 38 miRNAs to target 148 host genes is experimentally validated. Six anti-viral miRNAs, namely, hsa-miR-1-3p, hsa-miR-17-5p, hsa-miR-199a-3p, hsa-miR-429, hsa-miR-15a-5p, and hsa-miR-20a-5p, are previously reported to be anti-viral in respiratory diseases and were found to be downregulated. The interaction network of the 2,197 human miRNAs and interacting transcription factors (TFs) enabled the identification of 51 miRNAs to interact with 77 TFs inducing activation or repression and affecting gene expression of linked genes. Further, from the gene regulatory network analysis, the top five hub genes HMOX1, DNMT1, PLAT, GDF1, and ITGB1 are found to be involved in interferon (IFN)-α2b induction, epigenetic modification, and modulation of anti-viral activity. The comparative miRNAs target identification analysis in other respiratory viruses revealed the presence of 98 unique host miRNAs targeting SARS-CoV-2 genome. Our findings identify prioritized key regulatory interactions that include miRNAs and TFs that provide opportunities for the identification of novel drug targets and development of anti-viral drugs.

Macrophage Phenotypes and Hepatitis B Virus Infection.

Globally, hepatitis B virus (HBV) infection and its related liver diseases account for 780,000 deaths every year. Outcomes of HBV infection depend on the interaction between the virus and host immune system. It is becoming increasingly apparent that Kupffer cells (KCs), the largest population of resident and monocyte-derived macrophages in the liver, contribute to HBV infection in various aspects. These cells play an important role not only in the anti-HBV immunity including virus recognition, cytokine production to directly inhibit viral replication and recruitment and activation of other immune cells involved in virus clearance but also in HBV outcome and progression, such as persistent infection and development of end-stage liver diseases. Since liver macrophages play multiple roles in HBV infection, they are directly targeted by HBV to benefit its life cycle. In the present review, we briefly outline the current advances of research of macrophages, especially the studies of their phenotypes, in chronic HBV infection.

Atypical Severe Shock-like Reactions in Adolescents After Trimethoprim-Sulfamethoxazole Therapy.

Severe drug hypersensitivity reactions to antibiotics are rare but trimethoprim-sulfamethoxazole (TMP-SMX) is uniquely associated with numerous and varied manifestations including a reaction resembling septic shock, first observed in human immunodeficiency virus (HIV)/AIDS patients. Over the past 25 years about 20 cases have been reported and an association with the virus and related immune system dysregulation was assumed. However, recent reports in adults have recognized similar shock-like reactions in non-HIV infected individuals. Here we review severe TMP-SMX hypersensitivity reactions and within the context of these known reactions, describe three non-HIV infected adolescent patients with shock-like reactions to TMP-SMX observed in one institution over 1.5 years.

SARS-CoV-2: An immunogenetics call to arms.

Susceptibility to viral infection, development of immunity, response to treatment and patient clinical outcomes are all under the control of heritable factors in the host. In the context of the current SARS‐Cov‐2 pandemic, this review considers existing immunogenetic knowledge of virus‐immune system interactions. A major focus is to highlight areas in which work is required in order to improve understanding of antiviral immune responses and to move towards improved patient management.

A juggernaut of innate & adaptive immune cells in chronic hepatitis C.

Hepatitis C virus (HCV) is a small positive-sense, single-stranded RNA virus, the causal organism for chronic hepatitis. Chronic hepatitis leads to inflammation of liver, causing cirrhosis, fibrosis and steatosis, which may ultimately lead to liver cancer in a few cases. Innate and adaptive immune responses play an important role in the pathogenesis of HCV infection, thus acting as an important component in deciding the fate of the disease. Numerous studies have indicated that the derangement of these immune responses results in the persistence of infection leading to chronic state of the disease. Interactions between virus and host immune system generally result in the elimination of virus, but as the virus evolves with different evading mechanisms, it makes environment favourable for its survival and replication. It has been reported that HCV impairs the immune system by functional modulation of the cells of innate as well as adaptive immune responses, resulting in chronic state of the disease, influencing the response to antiviral therapy in these patients. These defects in the immune system lead to suboptimal immune responses and therefore, impaired effector functions. This review highlights the involvement or association of different immune cells such as natural killer cells, B cells, dendritic cells and T cells in HCV infection and how the virus plays a role in manipulating certain regulatory mechanisms to make these cells dysfunctional for its own persistence and survival.

Systems analysis reveals complex biological processes during virus infection fate decisions.

The processes and mechanisms of virus infection fate decisions that are the result of a dynamic virus-immune system interaction with either an efficient effector response and virus elimination or an alleviated immune response and chronic infection are poorly understood. Here, we characterized the host response to acute and chronic lymphocytic choriomeningitis virus (LCMV) infections by gene coexpression network analysis of time-resolved splenic transcriptomes. First, we found an early attenuation of inflammatory monocyte/macrophage prior to the onset of T cell exhaustion, and second, a critical role of the XCL1-XCR1 communication axis during the functional adaptation of the T cell response to the chronic infection state. These findings not only reveal an important feedback mechanism that couples T cell exhaustion with the maintenance of a lower level of effector T cell response but also suggest therapy options to better control virus levels during the chronic infection phase.

How Computational Epitope Mapping Identifies the Interactions between Nanoparticles Derived from Papaya Mosaic Virus Capsid Proteins and Immune System.

Background: Nanoparticles derived from plant viruses possess fascinating structures, versa-tile functions and safe properties, rendering them valuable for a variety of applications. Papaya mosaic Virus-Like Particles (VLPs) are nanoparticles that contain a repetitive number of virus capsid proteins (PMV-CP) and are considered to be promising platforms for vaccine design. Previous studies have re-ported the antigenicity of PMV nanoparticles in mammalian systems.Materials and Methods: As experiments that concern vaccine development require careful design and can be time consuming, computational experiments are of particular importance. Therefore, prior to ex-pressing PMV-CP in E. coli and producing nanoparticles, we performed an in silico analysis of the virus particles using software programs based on a series of sophisticated algorithms and modeling networks as useful tools for vaccine design. A computational study of PMV-CP in the context of the immune sys-tem reaction allowed us to clarify particle structure and other unknown features prior to their introduc-tion in vitro.Results: The results illustrated that the produced nanoparticles can trigger an immune response in the absence of fusion with any foreign antigen.Conclusion: Based on the in silico analyses, the empty capsid protein was determined to be recognised by different B and T cells, as well as cells which carry MHC epitopes.

Global Dynamics of a Virus-Immune System with Virus-Guided Therapy and Saturation Growth of Virus

We considered a piecewise virus-immune dynamic model to investigate the effectiveness of the HIV virus loads-guided structured treatment interruptions (STIs). To better describe the biological reality, we extended the existing models by taking the carrying capacity of the virus loads into consideration to indicate the saturated growth of virus loads. We initially investigated the sliding dynamics of the proposed model and then obtained the global dynamics of the proposed model. Our main results showed that the system can exhibit very complex and diverse dynamic behaviors including a globally asymptotically stable equilibrium, bistable equilibra, and tristable equilibria, depending on the dynamics of the subsystems and the threshold level. In particular, an interesting result indicated that, with a proper threshold condition, the virus-guided therapy policy can successfully control the virus loads far below its carrying capacity and maintain the activity of the immune system for the case that the effector cells always go to zero without therapy or with continuous therapy. The finding suggested that the optimal strategy should be individual-based due to coexistence of multiple stable steady states, depending on the threshold conditions and the initial levels of viral loads and effector cells of the patients.

Insertion site of FLAG on foot-and-mouth disease virus VP1 G-H loop affects immunogenicity of FLAG

The G-H loop of the foot-and-mouth disease virus (FMDV) virion contains certain dominant immunogenic epitopes, as well as an arginine-glycine-aspartic acid (RGD) motif that is recognized by cell surface integrin receptors. Previous experiments indicate that it is critical to maintain virus structural integrity when inserting an exogenous epitope into the surface of an FMDV structural protein. However, it remains to be determined how factors such as different insertion positions affect interactions among the virus, cells and host immune system. In this study, one infectious cDNA clone of the swine FMDV Cathay topotype strain O/CHA/90 was constructed. Then, a FLAG marker (DYKDDDDK) was inserted upstream (–4) or downstream (+10) of the RGD motif to generate tagged viruses vFLAG-O/CHA/90 or vO/CHA/90-FLAG, investigating the possibility of expressing foreign antigen and effect on its immunogenicity. Compared to the parental virus, both tagged viruses exhibited similar plaque phenotypes, suckling mouse pathogenicity and antigenicity. Additionally, the FLAG tag insertion position did not change the use of integrin-mediated cell entry by the tagged viruses. Interestingly, both tagged vaccines protected pigs against challenge with the parental virus O/CHA/90 and induced immune responses against FMDV in BALB/c mice and pigs, but only vaccination with vFLAG-O/CHA/90 generated anti-FLAG antibodies. Our findings demonstrated that two sites (RGD–4 and RGD+10) tolerated the insertion of an exogenous gene in the swine FMDV O/CHA/90 strain. However, only RGD–4 was a novel and appropriate inserting site which could tolerate exogenous FLAG. The resultant tagged virus is a promising candidate for FMD vaccine which can be differentiating infected from vaccinated animals (DIVA).

Small Animal Models for Evaluating Filovirus Countermeasures.

The development of novel therapeutics and vaccines to treat or prevent disease caused by filoviruses, such as Ebola and Marburg viruses, depends on the availability of animal models that faithfully recapitulate clinical hallmarks of disease as it is observed in humans. In particular, small animal models (such as mice and guinea pigs) are historically and frequently used for the primary evaluation of antiviral countermeasures, prior to testing in nonhuman primates, which represent the gold-standard filovirus animal model. In the past several years, however, the filovirus field has witnessed the continued refinement of the mouse and guinea pig models of disease, as well as the introduction of the hamster and ferret models. We now have small animal models for most human-pathogenic filoviruses, many of which are susceptible to wild type virus and demonstrate key features of disease, including robust virus replication, coagulopathy, and immune system dysfunction. Although none of these small animal model systems perfectly recapitulates Ebola virus disease or Marburg virus disease on its own, collectively they offer a nearly complete set of tools in which to carry out the preclinical development of novel antiviral drugs.