Within-host Virus Research Articles

Hopf bifurcation of an age-structured virus infection model

In this paper, we introduce and analyze a mathematical model of a viral infection with explicit age-since infection structure for infected cells. We extend previous age-structured within-host virus models by including logistic growth of target cells and allowing for absorption of multiple virus particles by infected cells. The persistence of the virus is shown to depend on the basic reproduction number \begin{document}$R_{0}$\end{document} . In particular, when \begin{document}$R_{0}≤1$\end{document} , the infection free equilibrium is globally asymptotically stable, and conversely if \begin{document}$R_{0}> 1$\end{document} , then the infection free equilibrium is unstable, the system is uniformly persistent and there exists a unique positive equilibrium. We show that our system undergoes a Hopf bifurcation through which the infection equilibrium loses the stability and periodic solutions appear.

Environmental Nutrient Supply Directly Alters Plant Traits but Indirectly Determines Virus Growth Rate.

Ecological stoichiometry and resource competition theory both predict that nutrient rates and ratios can alter infectious disease dynamics. Pathogens such as viruses hijack nutrient rich host metabolites to complete multiple steps of their epidemiological cycle. As the synthesis of these molecules requires nitrogen (N) and phosphorus (P), environmental supply rates, and ratios of N and P to hosts can directly limit disease dynamics. Environmental nutrient supplies also may alter virus epidemiology indirectly by changing host phenotype or the dynamics of coinfecting pathogens. We tested whether host nutrient supplies and coinfection control pathogen growth within hosts and transmission to new hosts, either directly or through modifications of plant tissue chemistry (i.e., content and stoichiometric ratios of nutrients), host phenotypic traits, or among-pathogen interactions. We examined two widespread plant viruses (BYDV-PAV and CYDV-RPV) in cultivated oats (Avena sativa) grown along a range of N and of P supply rates. N and P supply rates altered plant tissue chemistry and phenotypic traits; however, environmental nutrient supplies and plant tissue content and ratios of nutrients did not directly alter virus titer. Infection with CYDV-RPV altered plant traits and resulted in thicker plant leaves (i.e., higher leaf mass per area) and there was a positive correlation between CYDV-RPV titer and leaf mass per area. CYDV-RPV titer was reduced by the presence of a competitor, BYDV-PAV, and higher CYDV-RPV titer led to more severe chlorotic symptoms. In our experimental conditions, virus transmission was unaffected by nutrient supply rates, co-infection, plant stoichiometry, or plant traits, although nutrient supply rates have been shown to increase infection and coinfection rates. This work provides a robust test of the role of plant nutrient content and ratios in the dynamics of globally important pathogens and reveals a more complex relationship between within-host virus growth and alterations of plant traits. A deeper understanding of the differential effects of environmental nutrient supplies on virus epidemiology and ecology is particularly relevant given the rapid increase of nutrients flowing into Earth's ecosystems as a result of human activities.

Pleiotropic Effects of Resistance-Breaking Mutations on Particle Stability Provide Insight into Life History Evolution of a Plant RNA Virus.

In gene-for-gene host-virus interactions, virus evolution to infect and multiply in previously resistant host genotypes, i.e., resistance breaking, is a case of host range expansion, which is predicted to be associated with fitness penalties. Negative effects of resistance-breaking mutations on within-host virus multiplication have been documented for several plant viruses. However, understanding virus evolution requires analyses of potential trade-offs between different fitness components. Here we analyzed whether coat protein (CP) mutations in Pepper mild mottle virus that break L-gene resistance in pepper affect particle stability and, thus, survival in the environment. For this purpose, CP mutations determining the overcoming of L 3 and L 4 resistance alleles were introduced in biologically active cDNA clones. The kinetics of the in vitro disassembly of parental and mutant particles were compared under different conditions. Resistance-breaking mutations variously affected particle stability. Structural analyses identified the number and type of axial and side interactions of adjacent CP subunits in virions, which explained differences in particle stability and contribute to understanding of tobamovirus disassembly. Resistance-breaking mutations also affected virus multiplication and virulence in the susceptible host, as well as infectivity. The sense and magnitude of the effects of resistance-breaking mutations on particle stability, multiplication, virulence, or infectivity depended on the specific mutation rather than on the ability to overcome the different resistance alleles, and effects on different traits were not correlated. Thus, the results do not provide evidence of links or trade-offs between particle stability, i.e., survival, and other components of virus fitness or virulence.IMPORTANCE The effect of survival on virus evolution remains underexplored, despite the fact that life history trade-offs may constrain virus evolution. We approached this topic by analyzing whether breaking of L-gene resistance in pepper by Pepper mild mottle virus, determined by coat protein (CP) mutations, is associated with reduced particle stability and survival. Resistance-breaking mutations affected particle stability by altering the interactions between CP subunits. However, the sense and magnitude of these effects were unrelated to the capacity to overcome different resistance alleles. Thus, resistance breaking was not traded with survival. Resistance-breaking mutations also affected virus fitness within the infected host, virulence, and infectivity in a mutation-specific manner. Comparison of the effects of CP mutations on these various traits indicates that there are neither trade-offs nor positive links between survival and other life history traits. These results demonstrate that trade-offs between life history traits may not be a general constraint in virus evolution.

The Mechanisms for Within-Host Influenza Virus Control Affect Model-Based Assessment and Prediction of Antiviral Treatment.

Models of within-host influenza viral dynamics have contributed to an improved understanding of viral dynamics and antiviral effects over the past decade. Existing models can be classified into two broad types based on the mechanism of viral control: models utilising target cell depletion to limit the progress of infection and models which rely on timely activation of innate and adaptive immune responses to control the infection. In this paper, we compare how two exemplar models based on these different mechanisms behave and investigate how the mechanistic difference affects the assessment and prediction of antiviral treatment. We find that the assumed mechanism for viral control strongly influences the predicted outcomes of treatment. Furthermore, we observe that for the target cell-limited model the assumed drug efficacy strongly influences the predicted treatment outcomes. The area under the viral load curve is identified as the most reliable predictor of drug efficacy, and is robust to model selection. Moreover, with support from previous clinical studies, we suggest that the target cell-limited model is more suitable for modelling in vitro assays or infection in some immunocompromised/immunosuppressed patients while the immune response model is preferred for predicting the infection/antiviral effect in immunocompetent animals/patients.

Full-genome dengue virus sequencing in mosquito saliva shows lack of convergent positive selection during transmission by Aedes aegypti.

Like other pathogens with high mutation and replication rates, within-host dengue virus (DENV) populations evolve during infection of their main mosquito vector, Aedes aegypti. Within-host DENV evolution during transmission provides opportunities for adaptation and emergence of novel virus variants. Recent studies of DENV genetic diversity failed to detect convergent evolution of adaptive mutations in mosquito tissues such as midgut and salivary glands, suggesting that convergent positive selection is not a major driver of within-host DENV evolution in the vector. However, it is unknown whether this conclusion extends to the transmitted viral subpopulation because it is technically difficult to sequence DENV genomes in mosquito saliva. Here, we achieved DENV full-genome sequencing by pooling saliva samples collected non-sacrificially from 49 to 163 individual Ae. aegypti mosquitoes previously infected with one of two DENV-1 genotypes. We compared the transmitted viral subpopulations found in the pooled saliva samples collected in time series with the input viral population present in the infectious blood meal. In all pooled saliva samples examined, the full-genome consensus sequence of the input viral population was unchanged. Although the pooling strategy prevents analysis of individual saliva samples, our results demonstrate the lack of strong convergent positive selection during a single round of DENV transmission by Ae. aegypti. This finding reinforces the idea that genetic drift and purifying selection are the dominant evolutionary forces shaping within-host DENV genetic diversity during transmission by mosquitoes.

Mathematical analysis of an HIV infection model including quiescent cells and periodic antiviral therapy

In this paper, we revisit the model by Guedj et al. [J. Guedj, R. Thibaut and D. Commenges, Maximum likelihood estimation in dynamical models of HIV, Biometrics 63 (2007) 198–206; J. Guedj, R. Thibaut and D. Commenges, Practical identifiability of HIV dynamics models, Bull. Math. Biol. 69 (2007) 2493–2513] which describes the effect of treatment with reverse transcriptase (RT) inhibitors and incorporates the class of quiescent cells. We prove that there is a threshold value [Formula: see text] of drug efficiency [Formula: see text] such that if [Formula: see text], the basic reproduction number [Formula: see text] and the infection is cleared and if [Formula: see text], the infectious equilibrium is globally asymptotically stable. When the drug efficiency function [Formula: see text] is periodic and of the bang–bang type we establish a threshold, in terms of spectral radius of some matrix, between the clearance and the persistence of the disease. As stated in related works [L. Rong, Z. Feng and A. Perelson, Emergence of HIV-1 drug resistance during antiretroviral treatment, Bull. Math. Biol. 69 (2007) 2027–2060; P. De Leenheer, Within-host virus models with periodic antiviral therapy, Bull. Math. Biol. 71 (2009) 189–210.], we prove that the increase of the drug efficiency or the active duration of drug must clear the infection more quickly. We illustrate our results by some numerical simulations.

Global dynamics for an age-structured HIV virus infection model with cellular infection and antiretroviral therapy

An age-structured within-host virus infection model with both virus-to-cell and cell-to-cell infection and antiretroviral therapy is investigated. The global stability analysis of the model is carried out in terms of the basic reproduction number R0 by constructing Lyapunov functionals. If R0≤1, the infection-free steady state is globally asymptotically stable; if R0>1, the infection steady state is globally asymptotically stable. The influence of drug therapy on cell-to-cell infection is discussed, which shows that cell-to-cell infection is important for the final outcome of the HIV virus infection and blocking cell-to-cell infection can effectively suppress the HIV virus spread. Moreover, numerical simulations are performed to study the dynamical behavior of solutions of the models. The results show that both the viral production rate and the death rate of infected cells play an important role in the viral dynamics of the model.

Global properties of nested network model with application to multi-epitope HIV/CTL dynamics.

Mathematical modeling and analysis can provide insight on the dynamics of ecosystems which maintain biodiversity in the face of competitive and prey-predator interactions. Of primary interests are the underlying structure and features which stabilize diverse ecological networks. Recently Korytowski and Smith (Theor Ecol 8(1):111-120, 2015) proved that a perfectly nested infection network, along with appropriate life history trade-offs, leads to coexistence and persistence of bacteria-phage communities in a chemostat model. In this article, we generalize their model in order to apply it to the within-host dynamics virus and immune response, in particular HIV and CTL (Cytotoxic T Lymphocyte) cells. Our model can describe sequential viral escape from dominant immune responses and rise in subdominant immune responses, consistent with observed patterns of HIV/CTL evolution. We find a Lyapunov function for the system which leads to rigorous characterization of persistent viral and immune variants, along with informing upon equilibria stability and global dynamics. Results are interpreted in the context of within-host HIV/CTL evolution and numerical simulations are provided.

Stability and Hopf bifurcation of a within-host chikungunya virus infection model with two delays

In this paper, a within-host chikungunya virus infection model with two delays is considered. The basic reproductive number R0 is formulated. If R0<1, the virus-free equilibrium is globally asymptotically stable and the disease always dies out. If R0>1, the global stability of the unique endemic equilibrium E1 is proved for the case without the time delay of antigenic stimulation, which can change the stability of E1 and lead to the existence of Hopf bifurcation. Furthermore, explicit formulae for determining the direction of Hopf bifurcation and the stability of bifurcating periodic solutions are established. Finally, some numerical simulations are presented to illustrate the results.

Minimizing $\mathcal R_0$ for in-host virus model with periodic combination antiviral therapy

The aim of this article is to provide formulas and properties of the basic reproduction number, $\mathcal R_0$, for a within-host virus model with periodic combination drug treatment. In particular, we extend and further results about how the phase difference between drug treatment can critically affect the asymptotic dynamics of model and corresponding $\mathcal R_0$. Our main theorem establishes that $\mathcal R_0$ is minimized for out-of-phase efficacies and maximized for in-phase efficacies in a special case where drug efficacies are ``bang-bang'' functions.

Nonstandard finite difference scheme for a diffusive within-host virus dynamics model with both virus-to-cell and cell-to-cell transmissions

In this paper, we first propose a diffusive within-host virus dynamics model with both virus-to-cell and cell-to-cell transmissions. Then, we consider the discretization of the model by using nonstandard finite difference scheme. It is then followed by the investigation of the global stability of the equilibria of the discrete model. Our study shows that if the basic reproduction number R0≤1, then the infection-free equilibrium is globally asymptotically stable; however if R0>1, then the infection equilibrium is globally asymptotically stable. Numerical simulations are presented to illustrate our theoretical results.

Quantifying influenza virus diversity and transmission in humans.

Influenza A virus is characterized by high genetic diversity.1–3 However, most of what we know about influenza evolution has come from consensus sequences sampled at the epidemiological scale4 that only represent the dominant virus lineage within each infected host. Less is known about the extent of intra-host virus diversity and what proportion is transmitted between individuals.5 To characterize those virus variants that achieve sustainable transmission in new hosts, we examined intra-host virus genetic diversity within household donor/recipient pairs from the first wave of the 2009 H1N1 pandemic when seasonal H3N2 was co-circulating. While the same variants were found in multiple members of the community, the relative frequencies of variants fluctuated, with patterns of genetic variation more similar within than between households. We estimated the effective population size of influenza A virus across donor/recipient pairs to be approximately 100–200 contributing members, which enabled the transmission of multiple lineages including antigenic variants.

An Integrative Analysis of Foot-and-Mouth Disease Virus Carriers in Vietnam Achieved Through Targeted Surveillance and Molecular Epidemiology.

Foot-and-mouth disease (FMD) is a major constraint to transboundary trade in animal products, yet much of its natural ecology and epidemiology in endemic regions is still poorly understood. To address this gap, a multidisciplinary, molecular and conventional epidemiological approach was applied to an investigation of endemic FMD in Vietnam. Within the study space, it was found that 22.3% of sampled ruminants had previously been infected with FMD virus (FMDV), of which 10.8% were persistent, asymptomatic carriers (2.4% of the total population). Descriptive data collected from targeted surveillance and a farm questionnaire showed a significantly lower prevalence of FMDV infection for dairy farms. In contrast, farms of intermediate size and/or history of infection in 2010 were at increased risk of FMD exposure. At the individual animal level, buffalo had the highest exposure risk (over cattle), and there was spatial heterogeneity in exposure risk at the commune level. Conversely, carrier prevalence was higher for beef cattle, suggesting lower susceptibility of buffalo to persistent FMDV infection. To characterize virus strains currently circulating in Vietnam, partial FMDV genomic (VP1) sequences from carrier animals collected between 2012 and 2013 (N=27) and from FMDV outbreaks between 2009 and 2013 (N=79) were compared by phylogenetic analysis. Sequence analysis suggested that within the study period, there were two apparent novel introductions of serotype A viruses and that the dominant lineage of serotype O in Vietnam shifted from SEA/Mya-98 to ME-SA/PanAsia. FMDV strains shared close ancestors with FMDV from other South-East Asian countries indicating substantial transboundary movement of the predominant circulating strains. Close genetic relationships were observed between carrier and outbreak viruses, which may suggest that asymptomatic carriers of FMDV contribute to regional disease persistence. Multiple viral sequences obtained from carrier cattle over a 1-year period had considerable within-animal genetic variation, indicating within-host virus evolution.

A within-host virus model with multiple infected stages under time-varying environments

HIV-1 infection and treatment may occur in the non-constant environment due to the time-varying drug susceptibility and growth of target cells. In this paper, we propose a within-host virus model with multiple stages for infected cells under time-varying environments, to study how the multiple infected stages affect on the counts of viral load and CD4+-T cells. We establish the sufficient conditions for both persistent HIV infection and clearance of HIV infection based on two positive constants R*, R*. When the system is under persistent infection, we further obtained detailed estimates of both the lower and upper bounds of the viral load and the counts of CD4+-T cells. Furthermore, numerical simulations are carried out to verify our analytical results and demonstrate the combined effects of multiple infected stages and non-constant environments, and reflect that both persistence and clearance of infection are possible when R* < 1 < R* holds. In particular, the numerical results exhibit the viral load of system with multiple infected stages may be less than that with single infected stage, and simulate the effect of time-varying environment of the autonomous system with multiple infected stages. We expect that our theoretical and simulation results can provide guidance for clinical therapy for HIV infections.

Deep sequencing of virus-derived small interfering RNAs and RNA from viral particles shows highly similar mutational landscapes of a plant virus population.

RNA viruses exist within a host as a population of mutant sequences, often referred to as quasispecies. Within a host, sequences of RNA viruses constitute several distinct but interconnected pools, such as RNA packed in viral particles, double-stranded RNA, and virus-derived small interfering RNAs. We aimed to test if the same representation of within-host viral population structure could be obtained by sequencing different viral sequence pools. Using ultradeep Illumina sequencing, the diversity of two coexisting Potato virus Y sequence pools present within a plant was investigated: RNA isolated from viral particles and virus-derived small interfering RNAs (the derivatives of a plant RNA silencing mechanism). The mutational landscape of the within-host virus population was highly similar between both pools, with no notable hotspots across the viral genome. Notably, all of the single-nucleotide polymorphisms with a frequency of higher than 1.6% were found in both pools. Some unique single-nucleotide polymorphisms (SNPs) with very low frequencies were found in each of the pools, with more of them occurring in the small RNA (sRNA) pool, possibly arising through genetic drift in localized virus populations within a plant and the errors introduced during the amplification of silencing signal. Sequencing of the viral particle pool enhanced the efficiency of consensus viral genome sequence reconstruction. Nonhomologous recombinations were commonly detected in the viral particle pool, with a hot spot in the 3' untranslated and coat protein regions of the genome. We stress that they present an important but often overlooked aspect of virus population diversity. This study is the most comprehensive whole-genome characterization of a within-plant virus population to date and the first study comparing diversity of different pools of viral sequences within a host. We show that both virus-derived small RNAs and RNA from viral particles could be used for diversity assessment of within-plant virus population, since they show a highly congruent portrayal of the virus mutational landscape within a plant. The study is an important baseline for future studies of virus population dynamics, for example, during the adaptation to a new host. The comparison of the two virus sequence enrichment techniques, sequencing of virus-derived small interfering RNAs and RNA from purified viral particles, shows the strength of the latter for the detection of recombinant viral genomes and reconstruction of complete consensus viral genome sequence.

Dromedary MERS-CoV replicates in human respiratory tissues

Dromedary MERS-CoV replicates in human respiratory tissues

Trade-offs between and within scales: environmental persistence and within-host fitness of avian influenza viruses.

Trade-offs between different components of a pathogen's replication and transmission cycle are thought to be common. A number of studies have identified trade-offs that emerge across scales, reflecting the tension between strategies that optimize within-host proliferation and large-scale population spread. Most of these studies are theoretical in nature, with direct experimental tests of such cross-scale trade-offs still rare. Here, we report an analysis of avian influenza A viruses across scales, focusing on the phenotype of temperature-dependent viral persistence. Taking advantage of a unique dataset that reports both environmental virus decay rates and strain-specific viral kinetics from duck challenge experiments, we show that the temperature-dependent environmental decay rate of a strain does not impact within-host virus load. Hence, for this phenotype, the scales of within-host infection dynamics and between-host environmental persistence do not seem to interact: viral fitness may be optimized on each scale without cross-scale trade-offs. Instead, we confirm the existence of a temperature-dependent persistence trade-off on a single scale, with some strains favouring environmental persistence in water at low temperatures while others reduce sensitivity to increasing temperatures. We show that this temperature-dependent trade-off is a robust phenomenon and does not depend on the details of data analysis. Our findings suggest that viruses might employ different environmental persistence strategies, which facilitates the coexistence of diverse strains in ecological niches. We conclude that a better understanding of the transmission and evolutionary dynamics of influenza A viruses probably requires empirical information regarding both within-host dynamics and environmental traits, integrated within a combined ecological and within-host framework.

Quantifying the Fitness Advantage of Polymerase Substitutions in Influenza A/H7N9 Viruses during Adaptation to Humans

Adaptation of zoonotic influenza viruses towards efficient human-to-human transmissibility is a substantial public health concern. The recently emerged A/H7N9 influenza viruses in China provide an opportunity for quantitative studies of host-adaptation, as human-adaptive substitutions in the PB2 gene of the virus have been found in all sequenced human strains, while these substitutions have not been detected in any non-human A/H7N9 sequences. Given the currently available information, this observation suggests that the human-adaptive PB2 substitution might confer a fitness advantage to the virus in these human hosts that allows it to rise to proportions detectable by consensus sequencing over the course of a single human infection. We use a mathematical model of within-host virus evolution to estimate the fitness advantage required for a substitution to reach predominance in a single infection as a function of the duration of infection and the fraction of mutant present in the virus population that initially infects a human. The modeling results provide an estimate of the lower bound for the fitness advantage of this adaptive substitution in the currently sequenced A/H7N9 viruses. This framework can be more generally used to quantitatively estimate fitness advantages of adaptive substitutions based on the within-host prevalence of mutations. Such estimates are critical for models of cross-species transmission and host-adaptation of influenza virus infections.

A Within-Host Virus Model with Periodic Multidrug Therapy

This paper is devoted to the investigation of the effects of periodic drug treatment on a standard within-host virus model. We first introduce the basic reproduction ratio for the model, and then show that the infection free equilibrium is globally asymptotically stable, and the disease eventually disappears if R0<1, while there exists at least one positive periodic state and the disease persists when R0>1. We also consider an optimization problem by shifting the phase of these drug efficacy functions. It turns out that shifting the phase can certainly affect the stability of the infection free steady state. A numerical study is performed to illustrate our analytic results.

Global analysis of age-structured within-host virus model

A mathematical model of a within-host viral infection with explicit age-since-infection structure for infected cells is presented. A global analysis of the model is conducted. It is shown that when the basic reproductive number falls below unity, the infection dies out. On the contrary, when the basic reproductive number exceeds unity, there exists a unique positive equilibrium that attracts all positive solutions of the model. The global stability analysis combines the existence of a compact global attractor and a Lyapunov function.