Free Virus Research Articles

Lyapunov approach and global stability of Ebola virus infection model of an individual cells population

Ebola virus is among the most dangerous and devastating threats to human health, causing a large number of fatalities. In this paper, a mathematical modelling for the dynamics of Ebola virus infectious of an individual is presented as a system of nonlinear differential equations. The model has two equilibrium states namely, virus free equilibrium (VFE) and virus persistence equilibrium (VPE) states. The Effective reproduction number was obtained. The conditions under which the virus-free-equilibrium is globally asymptotically stable with the approach of linear Lyapunov function are shown when the effective reproduction numbers is less than unity. The nonlinear Lyapunov approach is employed to show the global stability of the endemic equilibrium only when the effective reproduction number is greater than unity. It was found that VFE is globally asymptotically stable if effective reproduction numbers is less than unity and VPE is globally asymptotically stable if M<N, otherwise unstable if M>N.

Interaction of Type 1 Porcine Reproductive and Respiratory Syndrome Virus With In Vitro Derived Conventional Dendritic Cells.

The present study delineates the interaction of a typical PRRSV1.1 isolate 3267 (moderate virulence) with in vitro derived pig conventional dendritic cells, cDC1, cDC2, and a CD14+ population (designated as CD14+ DCs). cDC1 and cDC2 were not susceptible to 3267 infection, but a fraction of CD14+ DCs were infected. After exposure to the virus, all three DC types remained immature as determined by no increase of maturation molecules (MHC-I, MHC-II, CD80/86, CCR7), no release of cytokines, no modification of antigen presentation abilities, and no alteration of endocytic/phagocytic capabilities. However, when infected MARC-145 cells were used as a source of viral antigens, cDC2 and CD14+ DCs showed a significant increase in the expression of maturation molecules and substantial release of cytokines, notably IL-12/IL-23p40 (by both DC types) and IL-10 (by CD14+ DCs). To address the impact of PRRSV1 3267 on TLR3- and TLR7-mediated activation, cDC1, cDC2, and CD14+ DCs were inoculated by the virus (live or UV-inactivated) for 6 h prior to or simultaneously with the addition of poly I:C (TLR3 ligand) or gardiquimod (TLR7 ligand; not used for cDC1). Compared with using TLR ligand alone, combination with the virus did not result in any alteration to the maturation markers on all DC types but changed the cytokine response to either TLR3 or TLR7 ligand. Pre-exposure of cDC2 or CD14+ DCs to the live virus resulted in an increased production of IFN-α upon poly I:C stimulation, while pre-exposure to UV-inactivated virus tended to enhance the release of IL-10 upon gardiquimod stimulation. Simultaneous addition of the live virus and the TLR ligand either had no effect (mainly in cDC2) or impaired most of the cytokine release after gardiquimod stimulation (in CD14+ DCs). When used as antigen presenting cells, cDC2 pre-inoculated by the live virus before addition of gardiquimod impaired the proliferation of CD4–CD8– T cells. In the case of CD14+ DCs, pre-exposure to the live virus or simultaneously added with TLR3 or TLR7 ligand largely decreased the proliferation of CD4–CD8+ and CD4–CD8+ T-cell subsets. For cDC1, no significant changes were observed in cytokine responses or T-cell proliferation after poly I:C stimulation. Of note, cDC1 had a short life during in vitro culturing, for which the results obtained might be biased. Overall, exposure to PRRSV1 did not induce maturation of cDC1, cDC2, or CD14+ DCs, but modified TLR3 and TLR7-associated responses (except for cDC1), which may affect the development of adaptive immunity during PRRSV1 infection. Moreover, the sensing of infected cells was different from that of the free virus.

A delay model for persistent viral infections in replicating cells.

Persistently infecting viruses remain within infected cells for a prolonged period of time without killing the cells and can reproduce via budding virus particles or passing on to daughter cells after division. The ability for populations of infected cells to be long-lived and replicate viral progeny through cell division may be critical for virus survival in examples such as HIV latent reservoirs, tumor oncolytic virotherapy, and non-virulent phages in microbial hosts. We consider a model for persistent viral infection within a replicating cell population with time delay in the eclipse stage prior to infected cell replicative form. We obtain reproduction numbers that provide criteria for the existence and stability of the equilibria of the system and provide bifurcation diagrams illustrating transcritical (backward and forward), saddle-node, and Hopf bifurcations, and provide evidence of homoclinic bifurcations and a Bogdanov-Takens bifurcation. We investigate the possibility of long term survival of the infection (represented by chronically infected cells and free virus) in the cell population by using the mathematical concept of robust uniform persistence. Using numerical continuation software with parameter values estimated from phage-microbe systems, we obtain two parameter bifurcation diagrams that divide parameter space into regions with different dynamical outcomes. We thus investigate how varying different parameters, including how the time spent in the eclipse phase, can influence whether or not the virus survives.

Factors associated with behavioral intention of free and self-paid severe acute respiratory coronavirus virus 2 (SARS-CoV-2) vaccination based on the social cognitive theory among nurses and doctors in China.

To examine the associations between factors based on the social cognitive theory (SCT) and behavioral intention among doctors and nurses in China toward free and self-paid (600 RMB or US$91) severe acute respiratory coronavirus virus 2 (SARS-CoV-2) vaccination given 80% effectiveness and rare mild side effects. Cross-sectional study. Public hospitals. The study included 362 doctors and 1,702 nurses in major departments of 5 hospitals of 3 Chinese provinces. An anonymous online survey was conducted from October to November 2020, facilitated by hospital administrators through online WeChat/QQ working groups. Data on outcome expectations, self-efficacy, norms, and COVID-19-related work experiences were collected. Multivariate logistic regression models were used for data analyses. The logistic regression analysis showed that physical (eg, protective effect of vaccination) and self-evaluative outcome expectations (eg, anticipated regret), self-efficacy, norms (eg, descriptive norm, subjective norm, professional norm, and moral norm), and job satisfaction were significantly and positively associated with the free and self-paid SARS-CoV-2 vaccination intention outcomes among doctors and nurses, adjusted for background variables. Doctors who had engaged in COVID-19-related work reported higher self-paid vaccination intention. Health promotion is needed to improve the uptake of SARS-CoV-2 vaccination among healthcare workers. Such interventions may consider modifying the identified factors of vaccination intention, including strengthening perceived efficacy, positive feelings about vaccination, the need to avoid future regret, self-efficacy, and social norms. Future studies should examine the actual behavior patterns of SARS-CoV-2 vaccination, and the efficacy of promotion intervention should be tested in randomized controlled studies.

Dynamics Analysis of a Delayed HIV Infection Model with CTL Immune Response and Antibody Immune Response

In this paper, dynamics analysis of a delayed HIV infection model with CTL immune response and antibody immune response is investigated. The model involves the concentrations of uninfected cells, infected cells, free virus, CTL response cells, and antibody antibody response cells. There are three delays in the model: the intracellular delay, virus replication delay and the antibody delay. The basic reproductive number of viral infection, the antibody immune reproductive number, the CTL immune reproductive number, the CTL immune competitive reproductive number and the antibody immune competitive reproductive number are derived. By means of Lyapunov functionals and LaSalle’s invariance principle, sufficient conditions for the stability of each equilibrium is established. The results show that the intracellular delay and virus replication delay do not impact upon the stability of each equilibrium, but when the antibody delay is positive, Hopf bifurcation at the antibody response and the interior equilibrium will exist by using the antibody delay as a bifurcation parameter. Numerical simulations are carried out to justify the analytical results.

Anti-TMV Activities of Pantoea agglomerans Lipopolysaccharides in vitro

Today there are no antiviral drugs of chemical nature that can completely cure virus-infected plants. The fact that their effect is limited to minimizing the pathogenic effect of viruses motivates many researchers to look for alternatives. In recent years it has been shown that lipopolysaccharides (LPS) of some bacteria, in particular representatives of the Pseudomonas genus were active against Tobacco mosaic virus (TMV). Therefore, we were interested in the additional study of LPS of phytopathogenic bacteria Pantoea agglomerans as a possible drug acting as antiviral agent. The aim of current study was to evaluate the antiviral activities of LPS obtained from phytopathogenic bacteria P. agglomerans against TMV in vitro. Methods. The antiviral activity of LPS preparations was investigated in vitro and assessed according to the inhibition percentage towards the number of local lesions in Datura stramonium leaves. P. agglomerans LPS was isolated from dry bacterial mass by phenol-water method. LPS mild acid degradation allowed to separate O-specific polysaccharide (OPS) and lipid A, which structures were identified by us earlier. The analysis of TMV and LPS interactions was carried out using a JEM 1400 transmission electron microscope (Jeol, Japan) at an accelerating voltage of 80 kV. Results. The most active were LPS preparations from P. agglomerans P324 and 8488. In vitro inhibitory efficacies of TMV infection by these LPS preparations was 59 and 60% respectively. LPS preparations of P. agglomerans 7969, 7604 and 9637, on the contrary, were inactive. Comparative analysis of the antiviral activity of LPS structural components of two P. agglomerans P324 and 7604 strains showed that the greatest inhibitory effect on the infectivity of TMV was exhibited by P. agglomerans P324 lipid A, the antiviral activity of which practically did not differ from the activity of the LPS molecule (it was lower by 7%). At the same time, the inhibitory effect of P. agglomerans 7604 core oligosaccharide (OG-core) against TMV was slightly higher compared to the effect of the whole LPS molecule. It can be assumed that the OG-core stimulated the defense mechanisms of plants and prevented the development of viral infection. Electron microscopic dates have shown that P. agglomerans P324 LPS at the concentration of 1 mg/ml influenced on freely located virions in the control causing “sticking” thus forming dense clusters, complexes or “bundles” of the virus. The individual structural components of P. agglomerans P324 LPS (lipid A and OG-core) did not have the same effect as a whole molecule. Conclusions. The study of the antiviral activity of LPS in the model system TMV – Datura stramonium L. plants showed that the most active were LPS preparations of only two strains of P. agglomerans (P324 and 8488) while the other seven strains were inactive. Individual structural components: lipid A from P. agglomerans P324 and OG-core from P. agglomerans 7604 decreased the infectivity of TMV by 7 and 15% higher than the initial LPS molecule. According to electron microscopy data the virions sticked together forming the dense clusters in case of the direct LPS-virus contacting in vitro whereas in the control it was observed just a single free virus particles. A more detailed study of the effect of individual structural components will help to understand the regularities of the LPS structure effect on TMV infectivity.

Emerging Pathogenic Unit of Vesicle-Cloaked Murine Norovirus Clusters is Resistant to Environmental Stresses and UV254 Disinfection

An individual virion was long believed to act as an independent infectious unit in virology, until the recent discovery of vesicle-cloaked virus clusters which has greatly challenged this central paradigm. Vesicle-cloaked virus clusters (also known as viral vesicles) are phospholipid-bilayer encapsulated fluid sacs that contain multiple virions or multiple copies of viral genomes. Norovirus is a global leading causative agent of gastroenteritis, and the reported prevalence of vesicle-cloaked norovirus clusters in stool has raised concerns whether the current disinfection, sanitation, and hygiene practices can effectively control environmental pollution by these pathogenic units. In this study, we have demonstrated that vesicle-cloaked murine norovirus (MNV-1) clusters were highly persistent under temperature variation (i.e., freeze-thaw) and they were partially resistant to detergent decomposition. MNV-1 vesicles were 1.89-3.17-fold more infectious in vitro than their free virus counterparts. Most importantly, MNV-1 vesicles were up to 2.16-times more resistant to UV254 disinfection than free MNV-1 at a low viral load in vitro. Interestingly, with the increase of the viral load, free MNV-1 and MNV-1 vesicles showed equivalent resistance to UV254 disinfection. We show that the increased multiplicity of infection provided by vesicles is in part responsible for these attributes. Our study, for the first time, sheds light on the environmental behavior of vesicle-cloaked virus clusters as unique emerging pathogenic units. Our study highlights the need to revisit current paradigms of disinfection, sanitation, and hygiene practices for protecting public health.

Viruses and viral infection of heterotrophic prokaryotes in shelf waters of the western part of the East Siberian Sea

In September 2017, studies were conducted in the East Siberian Sea along the transect from a Indigirka delta to the ice edge at the outer shelf margin. The abundances of planktonic prokaryotes (NPR) and free viruses (NV), frequency of visibly infected prokaryotic cells (FVIC), and virus-mediated mortality of prokaryotes (VMPR) varied within (0.5–3.4) × 106 (on average (1.67 ± 0.69) × 106) cells/mL; (2.3–10.3) × 106 (on average (5.28 ± 1.91) × 106) viruses/mL; 0.6–2.5 (on average 1.1 ± 0.4) % of NPR; and 4.5–22.3 (on average 9.0 ± 3.8) % of the total prokaryotic production, respectively. The proportions of viruses attached to prokaryotic cells (NVPR) and suspended particles (NVP) were 1.9–26.3 (on average 8.0 ± 5.0) % of NV and 0.1–65.9 (on average 8.0 ± 13.3) % of NV, respectively. High concentrations of detrital and mineral particles, to which a significant number of viruses were attached and, as a result, loss of their activity were recorded in the river–sea water mixing zone. In such a situation, the number of virus attacks on prokaryotes and cases of their infection decreased. There was a negative relationship between the concentration of suspended particles 0.5–5.0 μm in size and the abundance of infected prokaryotic cells. Thus, we conclude that viruses played a substantial role in controlling the abundance and production of heterotrophic prokaryotic plankton in the low-productive East Siberian Sea at the beginning of autumn. Regional index terms: Russian Federation; East Siberian Sea. Geographic bounding coordinates: 70–78° N; 150–165° E.

PEMODELAN VEISV DENGAN PENANGGULANGAN KARANTINA DAN VAKSINASI PADA PENYEBARAN VIRUS KOMPUTER

At this time computers and the Internet has become our daily needs, If the computer or the Internet network is disrupted, then it will interfere with our daily productivity. Usually computers and Internet will be disrupted if attacked by a virus, it can anticipate the computer's interference so as not to happen mass destruction on the computer or barriers to our daily productivity, we need to know the pattern of the spread of the Internet virus. Mathematical modelling can be one method to know the pattern of the spread of computer virus, so that if there is increasing the spread can be minimized. The models used in this study are VEISV models with Quarantine and Vaccination Enhancement. From the model get a reproduction number. Based on stability analysis of fixed point with criterion of Routh-Hurtwitz obtained first fixed point and second fixed point, then done arrangement of syntax to know rate of spread of computer virus. From the analysis results obtained the pattern of the spread of computer virus on virus free condition and virus infected.Keywords: Computer Virus, Quarantine and Vaccination, VEISV.

Analysis of drug treatment of the fractional HIV infection model of CD4+ T-cells

In this paper we consider fractional order model to HIV infection whose components are plasma densities of uninfected CD4+ T-cells, the infected such cells and the free virus. The main purpose of this work is to study the dynamic of fractional HIV infection of CD4+ T-cells with the impact of drug treatment. An iterative scheme based on the discretization of the domain and short memory principle is proposed to solve fractional HIV infection model numerically. The main reason for using this discretization technique is low computational cost and high accuracy compared to some other methods. Numerical results are presented graphically. Figures are used to show the behaviour of densities of uninfected and infected cells before and after the drug therapy. It is also shown that how the approximate solution varies from fractional order to integer order derivative. By listing CPU time in tabular form efficiency of the iterative scheme is shown. The proposed scheme is also effective in a long time period. The validation of results are shown by comparing results among the proposed technique, Runge Kutta Fourth order method, homotopy perturbation method, homotopy analysis method, Adam-Bashforth predictor-corrector method, Legendre wavelets operational matrix method and Laplace adomian-decomposition method.

Attenuation and transport of human enteric viruses and bacteriophage MS2 in alluvial sand and gravel aquifer media—laboratory studies

Potable groundwater contamination by human enteric viruses poses serious health risks. Our understanding of virus subsurface transport has largely depended on studying bacteriophages as surrogates. Few studies have compared the transport behaviour of enteric viruses, especially norovirus, with phage surrogates. We conducted laboratory column experiments to investigate norovirus and bacteriophage MS2 (MS2) filtration in alluvial sand, and rotavirus, adenovirus and MS2 filtration in alluvial gravel aquifer media in 2 mM NaCl (pH 6.6–6.9) with pore velocities of 4.6–5.4 m/day. The data were analysed using colloid filtration theory and HYDRUS-1D 2-site attachment-detachment modelling.Norovirus removal was somewhat lower than MS2 removal in alluvial sand. The removal of rotavirus and adenovirus was markedly greater than MS2 removal in alluvial gravel. These findings concurred with the log10 reduction values, mass recoveries, attachment efficiencies and irreversible deposition rate constants. The modelling results suggested that the MS2 detachment rates were in the same order of magnitude as norovirus, but they were 1 order of magnitude faster than those of rotavirus and adenovirus. The attachment of viruses and MS2 was largely reversible with faster detachment than attachment rates, favouring free virus transport. These findings highlight the risk associated with continual virus transport through subsurface media if viruses are not inactivated and remobilising previously attached viruses could trigger contamination events. Thus, virus attachment reversibility should be considered in virus transport predictions in subsurface media. Further research is needed to compare surrogates with enteric viruses, especially norovirus, regarding their transport behaviours under different experimental conditions.

Neuro-optimized numerical treatment of HIV infection model

In this paper, a neuro-optimized numerical method is presented for approximation of HIV virus progression model in the human body. The model is composed of coupled nonlinear system of differential equations (DEs) containing healthy and infected T-Cells and HIV free virus particles. The coupled system is transformed into feedforward artificial neural network (ANN) with Mexican hat wavelet function in the hidden layers. Two meta-heuristic algorithms based on chaotic particle swarm optimization (CPSO) and its hybrid version with local search technique are exploited to tune the parameters of ANN in an unsupervised manner of error function. A comprehensive testbed is established to observe the virus growth per day with performance metric containing fitness value, computational time complexity and convergence. The proposed solutions are compared with state of art Runge–Kutta method and Legendre Wavelet Collocation Method (LWCM). The core advantages of the proposed scheme are getting the solution on continuous grid, consistent convergence, simplicity in implementation and handling strong nonlinearity effectively.

Stochastic near-optimal control for drug therapy in a random viral model with cellular immune response

Viruses are responsible of illness. The purpose of drug therapy is to fight bacterial infection and to achieve definite outcomes that improve the patient’s quality of life. Mathematical models combined with clinical studies can be useful in forecasting infection and understanding viral infections mechanism among host cells. In this work, incorporating stochastic fluctuations, we consider a viral infection model to describe the role of lytic and nonlytic immune responses. Lytic immunity is defined as the destruction of infected cells. Nonlytic immunity is defined as the inhibition of viral replication by soluble mediators secreted by immune cells. Mainly, we investigate near optimal control for drug therapy. We show sufficient and necessary conditions for the near optimality. Then, by means of adjoint equations, we estimate the error bound for the near optimality. Numerical illustrations indicate that the antiviral drug therapy may induce a significant decrease of the peaks of infected cells and free virions.

SARS-CoV-2 and SARS-CoV Spike-Mediated Cell-Cell Fusion Differ in Their Requirements for Receptor Expression and Proteolytic Activation.

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infects cells through interaction of its spike protein (SARS2-S) with angiotensin-converting enzyme 2 (ACE2) and activation by proteases, in particular transmembrane protease serine 2 (TMPRSS2). Viruses can also spread through fusion of infected with uninfected cells. We compared the requirements of ACE2 expression, proteolytic activation, and sensitivity to inhibitors for SARS2-S-mediated and SARS-CoV-S (SARS1-S)-mediated cell-cell fusion. SARS2-S-driven fusion was moderately increased by TMPRSS2 and strongly by ACE2, while SARS1-S-driven fusion was strongly increased by TMPRSS2 and less so by ACE2 expression. In contrast to that of SARS1-S, SARS2-S-mediated cell-cell fusion was efficiently activated by batimastat-sensitive metalloproteases. Mutation of the S1/S2 proteolytic cleavage site reduced effector cell-target cell fusion when ACE2 or TMPRSS2 was limiting and rendered SARS2-S-driven cell-cell fusion more dependent on TMPRSS2. When both ACE2 and TMPRSS2 were abundant, initial target cell-effector cell fusion was unaltered compared to that of wild-type (wt) SARS2-S, but syncytia remained smaller. Mutation of the S2 cleavage (S2') site specifically abrogated activation by TMPRSS2 for both cell-cell fusion and SARS2-S-driven pseudoparticle entry but still allowed for activation by metalloproteases for cell-cell fusion and by cathepsins for particle entry. Finally, we found that the TMPRSS2 inhibitor bromhexine, unlike the inhibitor camostat, was unable to reduce TMPRSS2-activated cell-cell fusion by SARS1-S and SARS2-S. Paradoxically, bromhexine enhanced cell-cell fusion in the presence of TMPRSS2, while its metabolite ambroxol exhibited inhibitory activity under some conditions. On Calu-3 lung cells, ambroxol weakly inhibited SARS2-S-driven lentiviral pseudoparticle entry, and both substances exhibited a dose-dependent trend toward weak inhibition of authentic SARS-CoV-2.IMPORTANCE Cell-cell fusion allows viruses to infect neighboring cells without the need to produce free virus and contributes to tissue damage by creating virus-infected syncytia. Our results demonstrate that the S2' cleavage site is essential for activation by TMPRSS2 and unravel important differences between SARS-CoV and SARS-CoV-2, among those, greater dependence of SARS-CoV-2 on ACE2 expression and activation by metalloproteases for cell-cell fusion. Bromhexine, reportedly an inhibitor of TMPRSS2, is currently being tested in clinical trials against coronavirus disease 2019. Our results indicate that bromhexine enhances fusion under some conditions. We therefore caution against the use of bromhexine in high dosages until its effects on SARS-CoV-2 spike activation are better understood. The related compound ambroxol, which similarly to bromhexine is clinically used as an expectorant, did not exhibit activating effects on cell-cell fusion. Both compounds exhibited weak inhibitory activity against SARS-CoV-2 infection at high concentrations, which might be clinically attainable for ambroxol.

Lifestyle of sponge symbiont phages by host prediction and correlative microscopy

Bacteriophages (phages) are ubiquitous elements in nature, but their ecology and role in animals remains little understood. Sponges represent the oldest known extant animal-microbe symbiosis and are associated with dense and diverse microbial consortia. Here we investigate the tripartite interaction between phages, bacterial symbionts, and the sponge host. We combined imaging and bioinformatics to tackle important questions on who the phage hosts are and what the replication mode and spatial distribution within the animal is. This approach led to the discovery of distinct phage-microbe infection networks in sponge versus seawater microbiomes. A new correlative in situ imaging approach (‘PhageFISH-CLEM‘) localised phages within bacterial symbiont cells, but also within phagocytotically active sponge cells. We postulate that the phagocytosis of free virions by sponge cells modulates phage-bacteria ratios and ultimately controls infection dynamics. Prediction of phage replication strategies indicated a distinct pattern, where lysogeny dominates the sponge microbiome, likely fostered by sponge host-mediated virion clearance, while lysis dominates in seawater. Collectively, this work provides new insights into phage ecology within sponges, highlighting the importance of tripartite animal-phage-bacterium interplay in holobiont functioning. We anticipate that our imaging approach will be instrumental to further understanding of viral distribution and cellular association in animal hosts.

A compressive mathematical model including an eclipse stage of infected cells to study the impact of stem cells transplantation on one HIV1 patient

We propose a new mathematical model to study the effect of stem cells transplantation on HIV-1 patient as a system of first order nonlinear ordinary differential equations. We include in this model five populations: stem cells, free virus, productively infected cells, infected cells in the eclipse stage and non-infected T cells. The model admits two equilibrium states: a non-infected point and an endemically infected one. The study of the stability of the system before treatment is already known: If the “basic reproduction number” is smaller than 1, then the free disease point is asymptotically stable. If the “basic reproduction number” is greater than 1, then the endemic point is asymptotically stable. The study of the stability of the system after treatment proves that, for a patient with an initial “basic reproduction number”, greater than 1, if it is possible for the therapy to lower this ratio under 1, then the patient will recover. If it is not possible to lower the ratio under 1, the HIV infection persists, but, it is possible to offer to the patient a better life.

On the solution of the Human Immunodeficiency Virus (HIV) infection model using spectral collocation method

In this research work, we study the Human Immunodeficiency Virus (HIV) infection on helper T cells governed by a mathematical model consisting of a system of three first-order nonlinear differential equations. The objective of the analysis is to present an approximate mathematical solution to the model that gives the count of the numbers of uninfected and infected helper T cells and the number of free virus particles present at a given instant of time. The system of nonlinear ODEs is converted into a system of nonlinear algebraic equations using spectral collocation method with three different basis functions such as Chebyshev, Legendre and Jacobi polynomials. Some factors such as the production of helper T cells and infection of these cells play a vital role in infected and uninfected cell counts. Detailed error analysis is done to compare our results with the existing methods. It is shown that the spectral collocation method is a very reliable, efficient and robust method of solution compared to many other solution procedures available in the literature. All these results are presented in the form of tables and figures.

Quantifying the dynamics of viral recombination during free virus and cell-to-cell transmission in HIV-1 infection.

Recombination has been shown to contribute to human immunodeficiency virus-1 (HIV-1) evolution in vivo, but the underlying dynamics are extremely complex, depending on the nature of the fitness landscapes and of epistatic interactions. A less well-studied determinant of recombinant evolution is the mode of virus transmission in the cell population. HIV-1 can spread by free virus transmission, resulting largely in singly infected cells, and also by direct cell-to-cell transmission, resulting in the simultaneous infection of cells with multiple viruses. We investigate the contribution of these two transmission pathways to recombinant evolution, by applying mathematical models to in vitro experimental data on the growth of fluorescent reporter viruses under static conditions (where both transmission pathways operate), and under gentle shaking conditions, where cell-to-cell transmission is largely inhibited. The parameterized mathematical models are then used to extrapolate the viral evolutionary dynamics beyond the experimental settings. Assuming a fixed basic reproductive ratio of the virus (independent of transmission pathway), we find that recombinant evolution is fastest if virus spread is driven only by cell-to-cell transmission and slows down if both transmission pathways operate. Recombinant evolution is slowest if all virus spread occurs through free virus transmission. This is due to cell-to-cell transmission 1, increasing infection multiplicity; 2, promoting the co-transmission of different virus strains from cell to cell; and 3, increasing the rate at which point mutations are generated as a result of more reverse transcription events. This study further resulted in the estimation of various parameters that characterize these evolutionary processes. For example, we estimate that during cell-to-cell transmission, an average of three viruses successfully integrated into the target cell, which can significantly raise the infection multiplicity compared to free virus transmission. In general, our study points towards the importance of infection multiplicity and cell-to-cell transmission for HIV evolution.

Systematic Assessment of Antiviral Potency, Breadth, and Synergy of Triple Broadly Neutralizing Antibody Combinations against Simian-Human Immunodeficiency Viruses.

Daily burden and clinical toxicities associated with antiretroviral therapy (ART) emphasize the need for alternative strategies to induce long-term human immunodeficiency virus (HIV) remission upon ART cessation. Broadly neutralizing antibodies (bNAbs) can both neutralize free virions and mediate effector functions against infected cells and therefore represent a leading immunotherapeutic approach. To increase potency and breadth, as well as to limit the development of resistant virus strains, it is likely that bNAbs will need to be administered in combination. It is therefore critical to identify bNAb combinations that can achieve robust polyfunctional antiviral activity against a high number of HIV strains. In this study, we systematically assessed the abilities of single bNAbs and triple bNAb combinations to mediate robust polyfunctional antiviral activity against a large panel of cross-clade simian-human immunodeficiency viruses (SHIVs), which are commonly used as tools for validation of therapeutic strategies targeting the HIV envelope in nonhuman primate models. We demonstrate that most bNAbs are capable of mediating both neutralizing and nonneutralizing effector functions against cross-clade SHIVs, although the susceptibility to V3 glycan-specific bNAbs is highly strain dependent. Moreover, we observe a strong correlation between the neutralization potencies and nonneutralizing effector functions of bNAbs against the transmitted/founder SHIV CH505. Finally, we identify several triple bNAb combinations comprising of CD4 binding site-, V2-glycan-, and gp120-gp41 interface-targeting bNAbs that are capable of mediating synergistic polyfunctional antiviral activities against multiple clade A, B, C, and D SHIVs.IMPORTANCE Optimal bNAb immunotherapeutics will need to mediate multiple antiviral functions against a broad range of HIV strains. Our systematic assessment of triple bNAb combinations against SHIVs will identify bNAbs with synergistic, polyfunctional antiviral activity that will inform the selection of candidate bNAbs for optimal combination designs. The identified combinations can be validated in vivo in future passive immunization studies using the SHIV challenge model.

Polinton-like viruses are abundant in aquatic ecosystems

BackgroundPolintons are large mobile genetic elements found in the genomes of eukaryotic organisms that are considered the ancient ancestors of most eukaryotic dsDNA viruses. Originally considered as transposons, they have been found to encode virus capsid genes, suggesting they may actually be integrated viruses; however, an extracellular form has yet to be detected. Recently, circa 25 Polinton-like viruses have been discovered in environmental metagenomes and algal genomes, which shared distantly related genes to both Polintons and virophages (Lavidaviridae). These entities could be the first members of a major class of ancient eukaryotic viruses; however, owing to the lack of available genomes for analysis, information on their global diversity, evolutionary relationships, eukaryotic hosts, and status as free virus particles is limited.ResultsHere, we analysed the metaviromes of an alpine lake to show that Polinton-like virus genome sequences are abundant in the water column. We identify major capsid protein genes belonging to 82 new Polinton-like viruses and use these to interrogate publicly available metagenomic datasets, identifying 543 genomes and a further 16 integrated into eukaryotic genomes. Using an analysis of shared gene content and major capsid protein phylogeny, we define large groups of Polinton-like viruses and link them to diverse eukaryotic hosts, including a new group of viruses, which possess all the core genes of virophages and infect oomycetes and Chrysophyceae.ConclusionsOur study increased the number of known Polinton-like viruses by 25-fold, identifying five major new groups of eukaryotic viruses, which until now have been hidden in metagenomic datasets. The large enrichment (> 100-fold) of Polinton-like virus sequences in the virus-sized fraction of this alpine lake and the fact that their viral major capsid proteins are found in eukaryotic host transcriptomes support the hypothesis that Polintons in unicellular eukaryotes are viruses. In summary, our data reveals a diverse assemblage of globally distributed viruses, associated with a wide range of unicellular eukaryotic hosts. We anticipate that the methods we have developed for Polinton-like virus detection and the database of over 20,000 genes we present will allow for continued discovery and analysis of these new viral groups.4nQk6QRKxQCQHashEWMwNeVideo abstract