Viral Burst Size Research Articles

Tropism for ciliated cells is the dominant driver of influenza viral burst size in the human airway

Influenza viruses pose a significant burden on global human health. Influenza has a broad cellular tropism in the airway, but how infection of different epithelial cell types impacts replication kinetics and burden in the airways is not fully understood. Using primary human airway cultures, which recapitulate the diverse epithelial cell landscape of the human airways, we investigated the impact of cell type composition on virus tropism and replication kinetics. Cultures were highly diverse across multiple donors and 30 independent differentiation conditions and supported a range of influenza replication. Although many cell types were susceptible to influenza, ciliated and secretory cells were predominantly infected. Despite the strong tropism preference for secretory and ciliated cells, which consistently make up 75% or more of infected cells, only ciliated cells were associated with increased virus production. Surprisingly, infected secretory cells were associated with overall reduced virus output. The disparate response and contribution to influenza virus production could be due to different pro- and antiviral interferon-stimulated gene signatures between ciliated and secretory populations, which were interrogated with single-cell RNA sequencing. These data highlight the heterogeneous outcomes of influenza virus infections in the complex cellular environment of the human airway and the disparate impacts of infected cell identity on multiround burst size, even among preferentially infected cell types.

Influenza A viral burst size from thousands of infected single cells using droplet quantitative PCR (dqPCR).

An important aspect of how viruses spread and infect is the viral burst size, or the number of new viruses produced by each infected cell. Surprisingly, this value remains poorly characterized for influenza A virus (IAV), commonly known as the flu. In this study, we screened tens of thousands of cells using a microfluidic method called droplet quantitative PCR (dqPCR). The high-throughput capability of dqPCR enabled the measurement of a large population of infected cells producing progeny virus. By measuring the fully assembled and successfully released viruses from these infected cells, we discover that the viral burst sizes for both the seasonal H3N2 and the 2009 pandemic H1N1 strains vary significantly, with H3N2 ranging from 101 to 104 viruses per cell, and H1N1 ranging from 101 to 103 viruses per cell. Some infected cells produce average numbers of new viruses, while others generate extensive number of viruses. In fact, we find that only 10% of the single-cell infections are responsible for creating a significant portion of all the viruses. This small fraction produced approximately 60% of new viruses for H3N2 and 40% for H1N1. On average, each infected cell of the H3N2 flu strain produced 709 new viruses, whereas for H1N1, each infected cell produced 358 viruses. This novel method reveals insights into the flu virus and can lead to improved strategies for managing and preventing the spread of viruses.

Genomic and biological insights of bacteriophages JNUWH1 and JNUWD in the arms race against bacterial resistance.

The coevolution of bacteria and bacteriophages has created a great diversity of mechanisms by which bacteria fight phage infection, and an equivalent diversity of mechanisms by which phages subvert bacterial immunity. Effective and continuous evolution by phages is necessary to deal with coevolving bacteria. In this study, to better understand the connection between phage genes and host range, we examine the isolation and genomic characterization of two bacteriophages, JNUWH1 and JNUWD, capable of infecting Escherichia coli. Sourced from factory fermentation pollutants, these phages were classified within the Siphoviridae family through TEM and comparative genomic analysis. Notably, the phages exhibited a viral burst size of 500 and 1,000 PFU/cell, with latent periods of 15 and 20 min, respectively. They displayed stability over a pH range of 5 to 10, with optimal activity at 37°C. The complete genomes of JNUWH1 and JNUWD were 44,785 bp and 43,818 bp, respectively. Phylogenetic analysis revealed their close genetic relationship to each other. Antibacterial assays demonstrated the phages' ability to inhibit E. coli growth for up to 24 h. Finally, through laboratory-driven adaptive evolution, we successfully identified strains for both JNUWH1 and JNUWD with mutations in receptors specifically targeting lipopolysaccharides (LPS) and the lptD gene. Overall, these phages hold promise as additives in fermentation products to counter E. coli, offering potential solutions in the context of evolving bacterial resistance.

The reproduction number and its probability distribution for stochastic viral dynamics.

We consider stochastic models of individual infected cells. The reproduction number, R, is understood as a random variable representing the number of new cells infected by one initial infected cell in an otherwise susceptible (target cell) population. Variability in R results partly from heterogeneity in the viral burst size (the number of viral progeny generated from an infected cell during its lifetime), which depends on the distribution of cellular lifetimes and on the mechanism of virion release. We analyse viral dynamics models with an eclipse phase: the period of time after a cell is infected but before it is capable of releasing virions. The duration of the eclipse, or the subsequent infectious, phase is non-exponential, but composed of stages. We derive the probability distribution of the reproduction number for these viral dynamics models, and show it is a negative binomial distribution in the case of constant viral release from infectious cells, and under the assumption of an excess of target cells. In a deterministic model, the ultimate in-host establishment or extinction of the viral infection depends entirely on whether the mean reproduction number is greater than, or less than, one, respectively. Here, the probability of extinction is determined by the probability distribution of R, not simply its mean value. In particular, we show that in some cases the probability of infection is not an increasing function of the mean reproduction number.

Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting: the RV217 acute infection cohort study

The CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the mechanisms remain unclear. The difficulty in elucidating the evolutionary origin of the earliest X4 viruses limits our understanding of this phenomenon. We tracked the evolution of the transmitted/founder (T/F) HIV-1 in RV217 participants identified in acute infection. The origin of the X4 viruses was elucidated by single genome amplification, deep sequencing and coreceptor assay. Mutations responsible for coreceptor switch were confirmed by mutagenesis. Viral susceptibility to neutralization was determined by neutralization assay. Virus CD4 subset preference was demonstrated by sequencing HIV-1 RNA in sorted CD4 subsets. We demonstrated that the earliest X4 viruses evolved de novo from the T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive the X4 variants to replicate mainly in the central memory (CM) and naïve CD4 subsets. Likely due to the smaller viral burst size of the CM and naïve subsets, the X4 variants existed at low frequency in plasma. The origin of the X4 viruses preceded accelerated CD4 decline. All except one X4 virus identified in the current study lost the conserved V3 N301 glycan site. The findings demonstrate co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting which have implications for HIV-1 therapeutics and functional cure. The observations provide evidence that coreceptor switch can function as an evolutionary mechanism of immune evasion. Institute of Human Virology, National Institutes of Health, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Thai Red Cross AIDS Research Centre, Gilead Sciences, Merck, and ViiV Healthcare.

Application of ultrasensitive digital ELISA for p24 enables improved evaluation of HIV-1 reservoir diversity and growth kinetics in viral outgrowth assays

The advent of combined antiretroviral therapy (cART) has been instrumental in controlling HIV-1 replication and transmission and decreasing associated morbidity and mortality. However, cART alone is not able to cure HIV-1 due to the presence of long-lived, latently infected immune cells, which re-seed plasma viremia when cART is interrupted. Assessment of HIV-cure strategies using ex vivo culture methods for further understanding of the diversity of reactivated HIV, viral outgrowth, and replication dynamics are enhanced using ultrasensitive digital ELISA based on single-molecule array (Simoa) technology to increase the sensitivity of endpoint detection. In viral outgrowth assays (VOA), exponential HIV-1 outgrowth has been shown to be dependent upon initial virus burst size surpassing a critical growth threshold of 5100 HIV-1 RNA copies. Here, we show an association between ultrasensitive HIV-1 Gag p24 concentrations and HIV-1 RNA copy number that characterize viral dynamics below the exponential replication threshold. Single-genome sequencing (SGS) revealed the presence of multiple identical HIV-1 sequences, indicative of low-level replication occurring below the threshold of exponential outgrowth early during a VOA. However, SGS further revealed diverse related HIV variants detectable by ultrasensitive methods that failed to establish exponential outgrowth. Overall, our data suggest that viral outgrowth occurring below the threshold necessary for establishing exponential growth in culture does not preclude replication competence of reactivated HIV, and ultrasensitive detection of HIV-1 p24 may provide a method to detect previously unquantifiable variants. These data strongly support the use of the Simoa platform in a multi-prong approach to measuring latent viral burden and efficacy of therapeutic interventions aimed at an HIV-1 cure.

Mathematical modelling of chemovirotherapy cancer treatment

ABSTRACT This work investigates the synergistic effects of the combination of oncolytic virotherapy and chemotherapy on tumour cells. A mathematical model, in the form of ordinary differential equations, is developed, analysed and numerically simulated. Analytical results show that without treatment, a tumour would grow to its maximum size. Also, in the presence of a tumour microenvironment, chemotherapy and virotherapy on their own are incapable of clearing tumour cells but instead reduce the tumour concentration. However, with the use of chemovirotherapy treatment, all tumour cells are depleted. It is also demonstrated that as the virus burst size and infection rate are increased, many infected tumour cells are produced and make them more susceptible to the chemotherapeutic drug. Furthermore, successful combination therapy depends on the virus burst size, infection rate, and drug-infusion method. Numerical simulations affirm that chemovirotherapy is highly effective in combating cancer cells which is in agreement with some recent theoretical and experimental studies.

Characterization and comparative genomic analysis of novel lytic bacteriophages targeting Cronobacter sakazakii

Cronobacter sakazakii, a foodborne pathogen, can contaminate powdered infant formula (PIF) and cause life-threatening meningitis, necrotizing colitis and meningoencephalitis in infants. Bacteriophages are increasingly considered an efficient approach to target pathogenic microorganisms. In the current study, four virulent phages that can infect C. sakazakii were isolated from sewage samples, and their biological and complete genomic characteristics were analyzed. A comparative genomic analysis was performed to investigate the functional genes and phylogenetic evolution of the four phages. The results revealed that all four phages belonged to the Ackermannviridae family. Notably, the viral burst size of the phages ranged from 10 to 250 PFU/cell, following a latent period of 5 min to 20 min. Moreover, phages were stable over a pH range of 4 to 10 and a temperature range of 50 ℃ to 60 ℃. The full length of the complete genomes of the four phages ranged from 41,929 bp to 146,806 bp, containing lysis genes but no virulence genes. Phylogenetic tree analysis showed that the four phages were members of two distinct genetic groups with a significant genetic evolutionary distance between each C. sakazakii phage. Furthermore, the antibacterial assay revealed that all phages could inhibit the growth of C. sakazakii for up to 24 h. Taken together, the four phages have huge prospects as additives in dairy products to counter C. sakazakii.

Tumor treatment with chemo-virotherapy and MEK inhibitor: A mathematical model of Caputo fractional differential operator

Mitogen-activated protein kinase (MEK) inhibitors and oncolytic virotherapy are identified as promising cancer therapies that can enhance the efficacy of other cancer treatments. A few studies demonstrate that cancer cells proliferate when exposed to virotherapy with MEK inhibitors in an integer order model or without them in a fractional order model. None of them are intended to investigate tumor cell growth under the combined treatment strategy of chemo-virotherapy with a MEK inhibitor in a fractional order model. In this paper, a mathematical model based on fractional order ordinary differential equations (ODEs) is developed for the mutual interactions among tumor cells, as well as a therapeutic combination of chemotherapy, oncolytic viruses and the functional consequence of MEK inhibitor, to investigate how virotherapy could enhance chemotherapy under the action of MEK inhibitor. The numerical results show that virus burst size and MEK inhibitors have a noticeable impact on regulating the trend of tumor cell proliferation. While virotherapy responses to tumor cell proliferation are undoubtedly quicker than chemotherapeutic treatment responses, MEK intensity clearly affects the success of the treatment regimen. The results of this study can contribute to the development of a therapeutic strategy that combines MEK inhibitor functional monitoring with tumor cell growth control.

A diffusive cancer model with virotherapy: Studying the immune response and its analytical simulation

<abstract><p>New cancer therapies, methods and protocols are needed to treat affected patients. Oncolytic viral therapy is a good suggestion for such treatment. This paper proposes a diffusive cancer model with virotherapy and an immune response. This work aims to study the aforementioned model while theoretically including positivity, boundedness and stability, as well as to find the analytical solutions. The analytical solutions are found by using the tanh-expansion method. As a result, we realized that the relative immune cell killing rate can be controlled by the viral burst size. The viral burst size is the number of viruses released from each infected cell during cell lysis. The increasing diffusion of the activated immune system leads to an increase in the uninfected cells. The presented model can be used to study the combination of immunotherapy and virotherapy.</p></abstract>

Reduced salinity exacerbates the viral infection on the coccolithophorid Emiliania huxleyi at elevated pCO2

The blooms of coccolithophores are usually terminated by their viruses. However, little has been documented on the interplay between the host with virus under different environmental conditions. We investigated the relationship of Emiliania huxleyi (BOF92) and its virus (EhV99B1) after the coccolithophorid had acclimated to different levels of salinity (S35: 35‰; S25: 25‰) and CO2 (AC: 400 μatm; HC: 1000 μatm) for about 15 generations. Our results showed that the virus infection decreased the growth of E. huxleyi along with decreased photochemical efficiency and photosynthetic carbon fixation under all the combinations of the treatments. Lowered salinity exacerbated the impacts of the viral infection on the growth and photosynthetic performance of E. huxley. The elevated pCO2 appeared to have alleviated the impacts of the viral infection on its photosynthetic performance with enhanced levels of Fv/Fm, by about 49% under S35 and by about 16% under S25, respectively. Nevertheless, the elevated pCO2 enhanced the virus burst size by about 18% under the high and by about 46% under the low levels of salinity, respectively. It is concluded that reduced salinity under the elevated pCO2 exacerbates the impact of the virus on E. huxleyi, leading to the highest burst sizes and the lowest photosynthetic carbon fixation, and the enhanced photochemical efficiency and increased levels of Chl a under the elevated pCO2 could have facilitated the energy supply for the virus multiplication in the infected cells of E. huxleyi.

The ratio versus difference optimization and its implications for optimality theory.

Among the classical models of optimization, some models maximize the ratio of returns to investment and others maximize the difference between returns and investment. However, an understanding of under what conditions the ratio or the difference approaches are appropriate is still fragmentary. Under specific contexts, it has been stated that when the investable amount, but not the opportunity for investment, is perceived to be limiting, a ratio optimum is appropriate, whereas a difference optimum is appropriate when the opportunity for investment, but not the investable amount, is perceived to be limiting. The question is important because the strategies indicated by ratio optimum can be substantially different than the ones suggested by difference optimum. We make a general case here to examine and expand this principle and apply it to many evolutionary ecological problems including parental investment, offspring quality-quantity trade-off, nectar production, pollinator behavior viral burst size, and intracellular protein handling. We show that the ratio-difference distinction in optimization models resolves many long-standing debates and conundrums in evolution and behavior.

Modeling Virus and Bacteria Populations in Europa's Subsurface Ocean.

The search for life in the universe is often informed by the study of “extreme” environments on Earth, which provide analogs for habitable locations in the Solar System, and whose microbial inhabitants may therefore also serve as analogs for potential life forms in extraterrestrial milieus. Recent work has highlighted the ubiquity and importance of viral entities in terrestrial ecosystems, which calls for a greater understanding of the roles that viruses might play in hypothetical extraterrestrial biomes. While some studies have modeled the dynamics of viral and bacterial populations in icy ocean environments on Earth, previous work has yet to apply these findings to icy ocean worlds such as Jupiter’s moon Europa. It is commonly theorized that hydrothermal vents on Europa could produce the necessary reductants for chemosynthesis to take place on the ocean bottom. In the case that Europa’s ocean is a reductant-limited environment, how might reductants and organic matter reach the sub-ice region to power a more easily accessible ecosystem? Here, we propose a ‘viral elevator,’ a mechanism that functions similarly to the ‘viral shunt’ in Earth’s oceans, which could create and shuttle dissolved organic matter (DOM) to a hypothetical sub-ice biosphere through viral carriers. Current models of Europa’s ocean currents and stratification support the movement of DOM to the sub-ice biosphere. We adapt an existing model for bacterial and viral population dynamics in Earth’s Arctic sea ice to Europa and use parameters from various Arctic-based studies as proxies for Europa’s environment. We find that viral burst size has the most significant effect on the virus-to-bacteria ratio (VBR) and system longevity in closed systems (such as brine pockets within Europa’s icy crust), with higher burst sizes clearly increasing both. When applying our model to an open system with an influx of DOM from the viral elevator, we found that a steady-state system is attainable, with resulting sub-ice biofilms on the order of 0.1 mm thick (global equivalent layer). This has implications for future searches for life on Europa, given that life directly under the ice will be easier to detect and observe than life near the ocean bottom.

Bimodal Expression Patterns, and Not Viral Burst Sizes, Predict the Effects of Vpr on HIV-1 Proviral Populations in Jurkat Cells.

ABSTRACTIntegration site landscapes, clonal dynamics, and latency reversal with or without vpr were compared in HIV-1-infected Jurkat cell populations, and the properties of individual clones were defined. Clones differed in fractions of long terminal repeat (LTR)-active daughter cells, with some clones containing few to no LTR-active cells, while almost all cells were LTR active for others. Clones varied over 4 orders of magnitude in virus release per active cell. Proviruses in largely LTR-active clones were closer to preexisting enhancers and promoters than low-LTR-active clones. Unsurprisingly, major vpr+ clones contained fewer LTR-active cells than vpr− clones, and predominant vpr+ proviruses were farther from enhancers and promoters than those in vpr− pools. Distances to these marks among intact proviruses previously reported for antiretroviral therapy (ART)-suppressed patients revealed that patient integration sites were more similar to those in the vpr+ pool than to vpr− integrants. Complementing vpr-defective proviruses with vpr led to the rapid loss of highly LTR-active clones, indicating that the effect of Vpr on proviral populations occurred after integration. However, major clones in the complemented pool and its vpr− parent population did not differ in burst sizes. When the latency reactivation agents prostratin and JQ1 were applied separately or in combination, vpr+ and vpr− population-wide trends were similar, with dual-treatment enhancement being due in part to reactivated clones that did not respond to either drug applied separately. However, the expression signatures of individual clones differed between populations. These observations highlight how Vpr, exerting selective pressure on proviral epigenetic variation, can shape integration site landscapes, proviral expression patterns, and reactivation properties.

Growth Rate-dependent Cell Death of Diatoms due to Viral Infection and Their Subsequent Coexistence in a Semi-continuous Culture System.

Viral infections are a major factor in diatom cell death. However, the effects of viruses on diatom dynamics remain unclear. Based on laboratory studies, it is hypothesized that virus-induced diatom mortality is dependent on the diatom growth rate. The present study aimed to elucidate the relationship between the diatom growth rate and virus-induced mortality using model systems of the marine planktonic diatom, Chaetoceros tenuissimus and its infectious viruses. We also examined the fate of diatom populations in a semi-continuous dilution culture system, in which host growth rates were controlled at 0.69, 2.08, and 3.47 day–1. Diatom populations gradually decreased following the viral inoculation of each culture system, and virus-induced mortality inversely correlated with the diatom growth rate. Furthermore, the viral burst size was slightly higher in lower growth rate cultures. These results suggested that the host physiological status related to the growth rate affected viral infection and proliferation. Diatom populations were not completely lysed or washed out in any of the dilution systems; they showed steady growth in the presence of infectious viruses. This may be partially explained by defective interference particles from viruses and cell debris. The present results indicate that diatoms in dilution environments maintain their populations, even under viral pressure. Moreover, diatom populations with a low growth rate may partially sustain higher growth populations through nutrient recycling following virus-induced cell death. The results of the present study provide insights into diatom dynamics in natural environments in the presence of infectious viruses.

Oncolytic viral therapies and the delicate balance between virus-macrophage-tumour interactions: a mathematical approach

The success of oncolytic virotherapies depends on the tumour microenvironment, which contains a large number of infiltrating immune cells. In this theoretical study, we derive an ODE model to investigate the interactions between breast cancer tumour cells, an oncolytic virus (Vesicular Stomatitis Virus), and tumour-infiltrating macrophages with different phenotypes which can impact the dynamics of oncolytic viruses. The complexity of the model requires a combined analytical-numerical approach to understand the transient and asymptotic dynamics of this model. We use this model to propose new biological hypotheses regarding the impact on tumour elimination/relapse/persistence of: (i) different macrophage polarisation/re-polarisation rates; (ii) different infection rates of macrophages and tumour cells with the oncolytic virus; (iii) different viral burst sizes for macrophages and tumour cells. We show that increasing the rate at which the oncolytic virus infects the tumour cells can delay tumour relapse and even eliminate tumour. Increasing the rate at which the oncolytic virus particles infect the macrophages can trigger transitions between steady-state dynamics and oscillatory dynamics, but it does not lead to tumour elimination unless the tumour infection rate is also very large. Moreover, we confirm numerically that a large tumour-induced M1$\to$M2 polarisation leads to fast tumour growth and fast relapse (if the tumour was reduced before by a strong anti-tumour immune and viral response). The increase in viral-induced M2$\to$M1 re-polarisation reduces temporarily the tumour size, but does not lead to tumour elimination. Finally, we show numerically that the tumour size is more sensitive to the production of viruses by the infected macrophages.

A mathematical model for the role of macrophages in the persistence and elimination of oncolytic viruses

Replicating oncolytic viruses provide promising treatment strategies against cancer. However, the success of these viral therapies depends mainly on the complex interactions between the virus particles and the host immune cells. Among these immune cells, macrophages represent one of the first line of defence against viral infections. In this paper, we consider a mathematical model that describes the interactions between a commonly-used oncolytic virus, the Vesicular Stomatitis Virus (VSV), and two extreme types of macrophages: the pro-inflammatory M1 cells (which seem to resist infection with VSV) and the anti-inflammatory M2 cells (which can be infected with VSV). We first show the existence of bounded solutions for this differential equations model. Then we investigate the long-term behaviour of the model by focusing on steady states and limit cycles, and study changes in this long-term dynamics as we vary different model parameters. Moreover, through sensitivity analysis we show that the parameters that have the highest impact on the level of virus particles in the system are the viral burst size (from infected macrophages), the virus infection rate, the M1$\to$M2 polarisation rate, and the M1-induced anti-viral immunity.

Osmotic Concentration-Controlled Particle Uptake and Wrapping-Induced Lysis of Cells and Vesicles.

In vivo, high protein and ion concentrations determine the preferred volumes of cells, organelles, and vesicles. Deformations of their lipid-bilayer membranes by nanoparticle wrapping reduce the interior volumes available to solutes and thus induce large osmotic pressure differences. Osmotic concentration can therefore be an important control parameter for wrapping of nanoparticles. We employ a curvature-elasticity model of the membrane and contact interaction with spherical particles to study their wrapping at initially spherical vesicles. Although the continuous particle-binding transition is independent of the presence of solutes, the discontinuous envelopment transition shifts to higher adhesion strengths and the corresponding energy barrier increases with increasing osmotic concentration. High osmotic concentrations stabilize partial-wrapped, membrane-bound states for both, particle attachment to the inside and the outside. In this regime, wrapping of particles controls membrane tension, with power-law dependencies on osmotic concentration and adhesion strength. For high adhesion strengths, particle wrapping can lead to the opening of mechanosensitive channels in cell membranes and to lysis. Membrane tension-induced stabilization of partial-wrapped states as well as wrapping-induced lysis play important roles not only for desired mechano-bacteriocidal effects of engineered nanomaterials but may also determine viral burst sizes of bacteria and control endocytosis for mammalian cells.

Basic stochastic model for tumor virotherapy.

The complexity of oncolytic virotherapy arises from many factors. In this study, we incorporate environmental noise and stochastic effects to our basic deterministic model and propose a stochastic model for viral therapy in terms of Ito stochastic differential equations. We conduct a detailed analysis of the model using boundary methods. We find two combined parameters, one describes possibilities of eradicating tumors and one is an increasing function of the viral burst size, which serve as thresholds to classify asymptotical dynamics of the model solution paths. We show there are three ergodic invariant probability measures which correspond to equilibrium states of the deterministic model, and extra possibility to eradicate tumor due to strong variance of tumor growth rate and medium viral burst size. Numerical analysis demonstrates several typical solution paths with biological explanations. In addition, we provide some medical interpretations and implications.

Spatial Model for Oncolytic Virotherapy with Lytic Cycle Delay.

We formulate a mathematical model of functional partial differential equations for oncolytic virotherapy which incorporates virus diffusivity, tumor cell diffusion, and the viral lytic cycle based on a basic oncolytic virus dynamics model. We conduct a detailed analysis for the dynamics of the model and carry out numerical simulations to demonstrate our analytic results. Particularly, we establish the positive invariant domain for the [Formula: see text] limit set of the system and show that the model has three spatially homogenous equilibriums solutions. We prove that the spatially uniform virus-free steady state is globally asymptotically stable for any viral lytic period delay and diffusion coefficients of tumor cells and viruses when the viral burst size is smaller than a critical value. We obtain the conditions, for example the ratio of virus diffusion coefficient to that of tumor cells is greater than a value and the viral lytic cycle, is greater than a critical value, under which the spatially uniform positive steady state is locally asymptotically stable. We also obtain conditions under which the system undergoes Hopf bifurcations, and stable periodic solutions occur. We point out medical implications of our results which are difficult to obtain from models without combining diffusive properties of viruses and tumor cells with viral lytic cycles.