Free Virus Research Articles

A COVID-19 Infection Model Considering the Factors of Environmental Vectors and Re-Positives and Its Application to Data Fitting in Japan and Italy.

COVID-19, which broke out globally in 2019, is an infectious disease caused by a novel strain of coronavirus, and its spread is highly contagious and concealed. Environmental vectors play an important role in viral infection and transmission, which brings new difficulties and challenges to disease prevention and control. In this paper, a type of differential equation model is constructed according to the spreading functions and characteristics of exposed individuals and environmental vectors during the virus infection process. In the proposed model, five compartments were considered, namely, susceptible individuals, exposed individuals, infected individuals, recovered individuals, and environmental vectors (contaminated with free virus particles). In particular, the re-positive factor was taken into account (i.e., recovered individuals who have lost sufficient immune protection may still return to the exposed class). With the basic reproduction number R0 of the model, the global stability of the disease-free equilibrium and uniform persistence of the model were completely analyzed. Furthermore, sufficient conditions for the global stability of the endemic equilibrium of the model were also given. Finally, the effective predictability of the model was tested by fitting COVID-19 data from Japan and Italy.

Infection by exosome-carried Coxsackievirus B3 induces immune escape resulting in an aggravated pathogenesis

Increasing evidence has shown that extracellular vesicles or exosomes released from virus-infected cells contain viral particles, genomes, or other pathogenic factors that move to neighbor cells, contributing to virus dissemination and productive infection. Our recent study demonstrated that exosomes carrying CVB3 virions exhibited greater infection efficiency than free virions because they accessed various entry routes, overcoming restrictions to viral tropism. However, the pathogenicity of exosomes carried CVB3 and their effect on immunological properties have not yet been completely explained. In the current study, we sought to explore whether exosomes exert their effect on the CVB3-induced pathogenesis or evade the immune attack. Our results showed that exosomes-carried CVB3 could effectively infect viral receptor-negative immune cells in vivo, resulting in inducing immune system loss. Importantly, the exosomes-carried CVB3 had the ability to escape the neutralizing antibodies activity resulting in inducing the severe onset of myocarditis. Using the genetically engineered mouse with deficiency of exosomes, we observed that the exosomes-carried CVB3 reinforced an aggravated pathogenesis. By understanding how exosomes promote the course of viral disease, clinical applications of exosomes can be developed.

Porcine deltacoronavirus resists antibody neutralization through cell-to-cell transmission

ABSTRACT Porcine deltacoronavirus (PDCoV) is an emerging enteric coronavirus that has been reported to infect a variety of animals and even humans. Cell–cell fusion has been identified as an alternative pathway for the cell-to-cell transmission of certain viruses, but the ability of PDCoV to exploit this transmission model, and the relevant mechanisms, have not been fully elucidated. Herein, we provide evidence that cell-to-cell transmission is the main mechanism supporting PDCoV spread in cell culture and that this efficient spread model is mediated by spike glycoprotein-driven cell–cell fusion. We found that PDCoV efficiently spread to non-susceptible cells via cell-to-cell transmission, and demonstrated that functional receptor porcine aminopeptidase N and cathepsins in endosomes are involved in the cell-to-cell transmission of PDCoV. Most importantly, compared with non-cell-to-cell infection, the cell-to-cell transmission of PDCoV was resistant to neutralizing antibodies and immune sera that potently neutralized free viruses. Taken together, our study revealed key characteristics of the cell-to-cell transmission of PDCoV and provided new insights into the mechanism of PDCoV infection.

Computational methods for multiscale modelling of virus infection dynamics

Abstract Virus infection dynamics is governed by the processes on multiple scales: on the whole organism level, tissue level, and intracellular level. In this paper, we develop a multi-scale multi-compartment model of HIV infection in a simplified setting and the computational methods for numerical realization of the model. The multiscale model describes the processes from various scales and of different nature (cell motility, virus diffusion, intracellular virus replication). Intracellular replication model is based on a Markov chain with time-inhomogeneous propensities that depend on the extracellular level of virions. Reaction diffusion equations used to model free virion diffusion in the lymphoid tissue have moving sources, which are determined by the positions of the infected cells (immune cell motility model) and the rate of virion secretion from them (intracellular model). Immune cell motility model parameterizes the intercellular interaction forces, friction and the stochastic force of active cell motility. Together, this allows for a proper description of the intracellular stochasticity that propagates across multiple scales. A hybrid discrete-continuous stochastic-deterministic algorithm for simulation of the multiscale model based on the uniformization Monte Carlo method is implemented.

Inactivation Kinetics and Replication Cycle Inhibition of Coxsackievirus B5 by Free Chlorine.

The kinetics of coxsackievirus serotype B5 (CVB5) inactivation with free chlorine is characterized over a range of pH and temperature relevant to drinking water treatment with the primary goal of selecting experimental conditions used for assessing inactivation mechanisms. The inactivation kinetics identified in our study is similar to or slower than experimental data reported in the literature and thus provides a conservative representation of the kinetics of CVB5 inactivation for free chlorine that could be useful in developing future regulations for waterborne viral pathogens including adequate disinfection treatment for CVB5. Untreated and free chlorine-treated viruses, and host cells synchronized-infected with these viruses, are analyzed by a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) method with the goal of quantitatively investigating the effect of free chlorine exposure on viral genome integrity, attachment to host cell, and viral genome replication. The inactivation kinetics observed results from a combination of hindering virus attachment to the host cell, inhibition of one or more subsequent steps of the replication cycle, and possibly genome damage.

Photodynamic Inhibition of Herpes Simplex Virus 1 Infection by Tricationic Amphiphilic Porphyrin with a Long Alkyl Chain.

Photodynamic therapy (PDT) is broadly used to treat different tumors, and it is a rapidly developing approach to inactivating or inhibiting the replication of fungi, bacteria, and viruses. Herpes simplex virus 1 (HSV-1) is an important human pathogen and a frequently used model to study the effects of PDT on enveloped viruses. Although many photosensitizers (PSs) have been tested for their antiviral properties, analyses are usually limited to assessing the reduction in viral yield, and thus the molecular mechanisms of photodynamic inactivation (PDI) remain poorly understood. In this study, we investigated the antiviral properties of TMPyP3-C17H35, a tricationic amphiphilic porphyrin-based PS with a long alkyl chain. We show that light-activated TMPyP3-C17H35 can efficiently block virus replication at certain nM concentrations without exerting obvious cytotoxicity. Moreover, we show that the levels of viral proteins (immediate-early, early, and late genes) were greatly reduced in cells treated with subtoxic concentrations of TMPyP3-C17H35, resulting in markedly decreased viral replication. Interestingly, we observed a strong inhibitory effect of TMPyP3-C17H35 on the virus yield only when cells were treated before or shortly after infection. In addition to the antiviral activity of the internalized compound, we show that the compound dramatically reduces the infectivity of free virus in the supernatant. Overall, our results demonstrate that activated TMPyP3-C17H35 effectively inhibits HSV-1 replication and that it can be further developed as a potential novel treatment and used as a model to study photodynamic antimicrobial chemotherapy.

Mechanosensitive extrusion of Enterovirus A71-infected cells from colonic organoids

Enterovirus A71 causes severe disease upon systemic infection, sometimes leading to life-threatening neurological dysfunction. However, in most cases infection is asymptomatic and limited to the gastrointestinal tract, where virus is amplified for transmission. Picornaviruses have previously been shown to exit infected cells via either cell lysis or secretion of vesicles. Here we report that entire Enterovirus A71-infected cells are specifically extruded from the apical surface of differentiated human colon organoids, as observed by confocal microscopy. Differential sensitivity to chemical and peptide inhibitors demonstrated that extrusion of virus-infected cells is dependent on force sensing via mechanosensitive ion channels rather than apoptotic cell death. When isolated and used as inoculum, intact virus-containing extruded cells can initiate new infections. In contrast, when mechanical force sensing is inhibited, large amounts of free virus are released. Thus, extrusion of live, virus-infected cells from intact epithelial tissue is likely to benefit both the integrity of host tissues and the protected spread of this faecal–oral pathogen within and between hosts.

Sloppiness: Fundamental study, new formalism and its application in model assessment.

Computational modelling of biological processes poses multiple challenges in each stage of the modelling exercise. Some significant challenges include identifiability, precisely estimating parameters from limited data, informative experiments and anisotropic sensitivity in the parameter space. One of these challenges' crucial but inconspicuous sources is the possible presence of large regions in the parameter space over which model predictions are nearly identical. This property, known as sloppiness, has been reasonably well-addressed in the past decade, studying its possible impacts and remedies. However, certain critical unanswered questions concerning sloppiness, particularly related to its quantification and practical implications in various stages of system identification, still prevail. In this work, we systematically examine sloppiness at a fundamental level and formalise two new theoretical definitions of sloppiness. Using the proposed definitions, we establish a mathematical relationship between the parameter estimates' precision and sloppiness in linear predictors. Further, we develop a novel computational method and a visual tool to assess the goodness of a model around a point in parameter space by identifying local structural identifiability and sloppiness and finding the most sensitive and least sensitive parameters for non-infinitesimal perturbations. We demonstrate the working of our method in benchmark systems biology models of various complexities. The pharmacokinetic HIV infection model analysis identified a new set of biologically relevant parameters that can be used to control the free virus in an active HIV infection.

Numerical solutions of the HIV infection model of CD4(+) cells by Laguerre wavelets

In this study, we analyze the numerical solutions of the Human Immunodeficiency Virus (HIV) infection on helper T cells by using the Laguerre wavelet method. Our goal is to find accurate approximate results of the models that measure the number of helper infected and uninfected T cells as well as the number of free virus particles at a given time. We present two different models which are governed by three first order nonlinear differential equations with different parameters. We include an error analysis in order to compare the results with other methods available in the literature, and observe that the Laguerre wavelet method gives highly accurate results, is very easy to implement, hence efficient, in the solution of the type of problems indicated.

Enhanced viral infectivity and reduced interferon production are associated with high pathogenicity for influenza viruses.

Epidemiological and clinical evidence indicates that humans infected with the 1918 pandemic H1N1 influenza virus and highly pathogenic avian H5N1 influenza viruses often displayed severe lung pathology. High viral load and extensive infiltration of macrophages are the hallmarks of highly pathogenic (HP) influenza viral infections. However, it remains unclear what biological mechanisms primarily determine the observed difference in the kinetics of viral load and macrophages between HP and low pathogenic (LP) viral infections, and how the mechanistic differences are associated with viral pathogenicity. In this study, we develop a mathematical model of viral dynamics that includes the dynamics of different macrophage populations and interferon. We fit the model to in vivo kinetic data of viral load and macrophage level from BALB/c mice infected with an HP or LP strain of H1N1/H5N1 virus using Bayesian inference. Our primary finding is that HP viruses have a higher viral infection rate, a lower interferon production rate and a lower macrophage recruitment rate compared to LP viruses, which are strongly associated with more severe tissue damage (quantified by a higher percentage of epithelial cell loss). We also quantify the relative contribution of macrophages to viral clearance and find that macrophages do not play a dominant role in the direct clearance of free viruses although their role in mediating immune responses such as interferon production is crucial. Our work provides new insight into the mechanisms that convey the observed difference in viral and macrophage kinetics between HP and LP infections and establishes an improved model-fitting framework to enhance the analysis of new data on viral pathogenicity.

Interaction of Virus in Cancer Patients: A Theoretical Dynamic Model.

This study reports on a phase-space analysis of a mathematical model of tumor growth with the interaction between virus and immune response. In this study, a mathematical determination was attempted to demonstrate the relationship between uninfected cells, infected cells, effector immune cells, and free viruses using a dynamic model. We revealed the stability analysis of the system and the Lyapunov stability of the equilibrium points. Moreover, all endemic equilibrium point models are derived. We investigated the stability behavior and the range of attraction sets of the nonlinear systems concerning our model. Furthermore, a global stability analysis is proved either in the construction of a Lyapunov function showing the validity of the concerned disease-free equilibria or in endemic equilibria discussed by the model. Finally, a simulated solution is achieved and the relationship between cancer cells and other cells is drawn.

Microbial density-dependent viral dynamics and low activity of temperate phages in the activated sludge process

The ecological behavior of bacteriophages (phages), the most abundant biological entity in wastewater treatment systems, is poorly understood, especially that of temperate phages. Here, the temporal dynamics of lytic and temperate phages in a laboratory-scale activated sludge reactor with a sludge bulking issue was investigated using coupled sludge metagenomic and viromic analyses. The lysogenic fragments (prophages) identified were widely distributed in the reconstructed metagenome-assembled genomes (61.7%, n = 227). However, only 12.3% of the identified prophages experienced lysogenic-lytic switching, and the abundance contribution of prophages to free virus communities was only 0.02–0.3%, indicating low activity of temperate phages. Although the sludge community changed dramatically during reactor operation, no massive prophage induction events were detected. Statistical analyses showed strong correlations between sludge concentration and free virus and temperate phage communities, suggesting microbial density-dependent virus dynamics in the sludge microbiota.

HIV-1 is Transported into the Central Nervous System by Trafficking Infected Cells.

In this work, we carried out a cross-sectional study examining HIV-1 and HCV free virus concentrations in blood and cerebrospinal fluid (CSF) to determine whether HIV-1 enters the central nervous system (CNS) passively as virus particles or in the context of migrating infected cells. If virions migrate freely across the blood-cerebrospinal fluid barrier (BCSFB) or the blood-brain barrier (BBB) then HCV and HIV-1 would be detectable in the CSF at proportions similar to that in the blood. Alternatively, virus entry as an infected cell would favor selective entry of HIV-1. We measured HIV-1 and HCV viral loads in the CSF and blood plasma of 4 co-infected participants who were not on antiviral regimens for either infection. We also generated HIV-1 env sequences and performed phylogenetic analyses to determine whether HIV-1 populations in the CSF of these participants were being maintained by local replication. While CSF samples taken from all participants had detectable levels of HIV-1, HCV was not detectable in any of the CSF samples despite participants having HCV concentrations in their blood plasma, which exceeded that of HIV-1. Further, there was no evidence of compartmentalized HIV-1 replication in the CNS (Supplementary Figure 1). These results are consistent with a model where HIV-1 particles cross the BBB or the BCSFB within infected cells. In this scenario, we would expect HIV-1 to reach the CSF more readily because the blood contains a much greater number of HIV-infected cells than HCV-infected cells. HCV entry into the CSF is restricted, indicating that virions do not freely migrate across these barriers and supporting the concept that HIV-1 is transported across the BCSFB and/or BBB by the migration of HIV-infected cells as part of an inflammatory response or normal surveillance.

Exosomes mediate Coxsackievirus B3 transmission and expand the viral tropism

Specific virus-receptor interactions are important determinants in viral host range, tropism and pathogenesis, influencing the location and initiation of primary infection as well as viral spread to other target organs/tissues in the postviremic phase. Coxsackieviruses of Group B (CVB) and its six serotypes (CVB1-6) specifically interact with two receptor proteins, coxsackievirus-adenovirus receptor (CAR) and decay-accelerating factor (DAF), and cause various lesions in most permissive tissues. However, our previous data and other studies revealed that virus receptor-negative cells or tissues can be infected with CVB type 3 (CVB3), which can also effectively replicate. To study this interesting finding, we explored the possibility that exosomes are involved in CVB3 tropism and that exosomes functionally enhance CVB3 transmission. We found that exosomes carried and delivered CVB3 virions, resulting in efficient infection in receptor-negative host cells. We also found that delivery of CVB3 virions attached to exosomes depended on the virus receptor CAR. Importantly, exosomes carrying CVB3 virions exhibited greater infection efficiency than free virions because they accessed various entry routes, overcoming restrictions to viral tropism. In vivo experiments demonstrated that inhibition of exosome coupling with virions attenuated CVB3-induced immunological system dysfunction and reduced mortality. Our study describes a new mechanism in which exosomes contribute to viral tropism, spread, and pathogenesis.

Stationary distribution and extinction of a stochastic HLIV model with viral production and Ornstein–Uhlenbeck process

In the past few decades, the human immunodeficiency virus (HIV), as a deadly pathogen, has imposed great harmful effects on human health. In addition, from the viewpoint of the microscopic, the interference of random factor exists in the process of virus replication. However, there are few works devoted to the theoretical studies of viral infection models with biologically reasonable stochastic effects yet. To study the effects of stochastic perturbations on the pathogenesis process of HIV/AIDS, in this paper, we develop and study a stochastic HLIV model with viral production and Ornstein–Uhlenbeck process, in which we assume that the conversion rate from an eclipse-phase cell to an infected cell satisfies the Ornstein–Uhlenbeck process. Firstly, by using the existence and uniqueness theory of solutions, we prove that there is a unique global solution to the stochastic model for any initial value. Then we use stochastic Lyapunov function methods and Fatou lemma to establish sufficient conditions for the existence of a stationary distribution of positive solutions to the stochastic system, which reflects the strong persistence of the disease. In addition, by adopting the comparison theorem of one-dimensional stochastic differential equation and the theory of ergodicity, we obtain sufficient conditions for complete eradication of the infected cells and free viruses. Our theoretical results show that the bigger speed of reversion or the smaller intensity of volatility is conducive to clearing infected cells and free viruses while the larger intensity of volatility or the smaller speed of reversion is not. We also find that this way of introducing stochastic perturbations is reasonable from the perspective of mathematics and biology. Finally, numerical simulations are carried out to demonstrate our main results. The modeling and methods can be applied to study other multigroup viral infection models or epidemic model with Ornstein–Uhlenbeck process, such as S-DI-A model, DS-I-A model, DS-DI-A model, SEI epidemic model, et al.

Analysis of a stochastic HIV model with cell-to-cell transmission and Ornstein–Uhlenbeck process

In this paper, we establish and analyze a stochastic human immunodeficiency virus model with both virus-to-cell and cell-to-cell transmissions and Ornstein–Uhlenbeck process, in which we suppose that the virus-to-cell infection rate and the cell-to-cell infection rate satisfy the Ornstein–Uhlenbeck process. First, we validate that there exists a unique global solution to the stochastic model with any initial value. Then, we adopt a stochastic Lyapunov function technique to develop sufficient criteria for the existence of a stationary distribution of positive solutions to the stochastic system, which reflects the strong persistence of all CD4+ T cells and free viruses. In particular, under the same conditions as the existence of a stationary distribution, we obtain the specific form of the probability density around the quasi-chronic infection equilibrium of the stochastic system. Finally, numerical simulations are conducted to validate these analytical results. Our results suggest that the methods used in this paper can be applied to study other viral infection models in which the infected CD4+ T cells are divided into latently infected and actively infected subgroups.

Numerical Procedure for Fractional HBV Infection with Impact of Antibody Immune

The current investigations are presented to solve the fractional order HBV differential infection system (FO-HBV-DIS) with the response of antibody immune using the optimization based stochastic schemes of the Levenberg-Marquardt backpropagation (LMB) neural networks (NNs), i.e., LMBNNs. The FO-HBV-DIS with the response of antibody immune is categorized into five dynamics, healthy hepatocytes (H), capsids (D), infected hepatocytes (I), free virus (V) and antibodies (W). The investigations for three different FO variants have been tested numerically to solve the nonlinear FO-HBV-DIS. The data magnitudes are implemented 75% for training, 10% for certification and 15% for testing to solve the FO-HBV-DIS with the response of antibody immune. The numerical observations are achieved using the stochastic LMBNNs procedures for soling the FO-HBV-DIS with the response of antibody immune and comparison of the results is presented through the database Adams-Bashforth-Moulton approach. To authenticate the validity, competence, consistency, capability and exactness of the LMBNNs, the numerical presentations using the mean square error (MSE), error histograms (EHs), state transitions (STs), correlation and regression are accomplished.

Partly inhibiting of blow-up by chemotactic repulsion in a cross-diffusion model for virus infection

This work extends the May-Nowak model for virus dynamics to a cross-diffusion version, additionally illustrating diffusion in all components and chemotactically biased migration of healthy cells toward density gradients of infected cells as well as the repulsion of free viruses by infected cells, in which a quasi-steady-state approximation is applied to the equation describing the evolution of infected cells. It is firstly proven that for any given suitably regular initial data and for fixed other model parameters, one can find a number $ \chi_0>0 $ such that whenever the attractive chemotaxis coefficient $ \chi $ satisfying $ \chi\le \chi_0 $, the corresponding spatially two-dimensional no-flux initial-boundary problem admits a global classical solution that is uniform bounded. Moreover, our numerical simulations show that when the attractive chemotaxis coefficient $ \chi $ is sufficiently large, the solution blows up in a finite time; on the other hand, our numerical results also imply that the above-mentioned repulsion can partially suppress the blow-up in some sense.

Disease Spread among Hunted and Retaliating Herding Prey

Two new ecoepidemic models of predator–prey type are introduced. They feature prey that gather in herds. The specific novelty consists of the fact that the prey also has the ability to defend themselves if they are in large numbers. The two deterministic models differ in the way a disease spreading among the ecosystem is transmitted, either by direct contact among infected and susceptible animals or by the intake of a virus present in the environment. Only the disease-free and the endemic equilibrium are allowed, and they are analyzed for feasibility and stability. The boundedness results allow us to gather some results regarding global stability. Persistent oscillations can be triggered when some relevant model parameters cross specific thresholds, causing repeated epidemic outbreaks. Furthermore, the environmental contamination through a free viruses destabilizes the endemic equilibrium and may lead to large amplitude oscillations, which are dangerous because they are potentially harmful to ecosystems. The bifurcation parameters leading to the limit cycle onset are related to the epidemics. For instance, they could be the disease-related mortality and the transmission rates, whether by direct contact among individuals or through the environment. The results of this investigation may provide insights to theoretical ecologists and may provide useful indications for epidemic spread containment.

Presence of Intact Hepatitis B Virions in Exosomes

Hepatitis B virus (HBV) was identified as an enveloped DNA virus with a diameter of 42 nm. Multivesicular bodies play a central role in HBV egress and exosome biogenesis. In light of this, it was studied whether intact virions wrapped in exosomes are released by HBV-producing cells. Robust methods for efficient separation of exosomes from virions were established. Exosomes were subjected to limited detergent treatment for release of viral particles. Electron microscopy of immunogold labeled ultrathin sections of purified exosomes was performed for characterization of exosomal HBV. Exosome formation/release was affected by inhibitors or Crispr/Cas-mediated gene silencing. Infectivity/uptake of exosomal HBV was investigated in susceptible and non-susceptible cells. Exosomes could be isolated from supernatants of HBV-producing cells, which are characterized by the presence of exosomal and HBV markers. These exosomal fractions could be separated from the fractions containing free virions. Limited detergent treatment of exosomes causes stepwise release of intact HBV virions and naked capsids. Inhibition of exosome morphogenesis impairs the release of exosome-wrapped HBV. Electron microscopy confirmed the presence of intact virions in exosomes. Moreover, the presence of large hepatitis B virus surface antigen on the surface of exosomes derived from HBV expressing cells was observed, which conferred exosome-encapsulated HBV initiating infection in susceptible cells in a , large hepatitis B virus surface antigen/Na+-taurocholate co-transporting polypeptide-dependent manner. The uptake of exosomal HBV with low efficiency was also observed in non-permissive cells. These data indicate that a fraction of intact HBV virions can be released as exosomes. This reveals a so far not described release pathway for HBV.