7,878 research outputs found
A Simulation Framework to Investigate in vitro Viral Infection Dynamics
AbstractVirus infection is a complex biological phenomenon for which in vitro experiments provide a uniquely concise view where data is often obtained from a single population of cells, under controlled environmental conditions. Nonetheless, data interpretation and real understanding of viral dynamics is still hampered by the sheer complexity of the various intertwined spatio-temporal processes. In this paper we present a tool to address these issues: a cellular automata model describing critical aspects of in vitro viral infections taking into account spatial characteristics of virus spreading within a culture well. The aim of the model is to understand the key mechanisms of SARS-CoV infection dynamics during the first 24hours post infection. We interrogate the model using a Latin Hypercube sensitivity analysis to identify which mechanisms are critical to the observed infection of host cells and the release of measured virus particles
Experimental and computational analyses reveal that environmental restrictions shape HIV-1 spread in 3D cultures
Here, using an integrative experimental and computational approach, Imle et al. show how cell motility and density affect HIV cell-associated transmission in a three-dimensional tissue-like culture system of CD4+ T cells and collagen, and how different collagen matrices restrict infection by cell-free virions
Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology.
Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose-concentration-effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future
Endemicity and prevalence of multipartite viruses under heterogeneous between-host transmission
Multipartite viruses replicate through a puzzling evolutionary strategy.
Their genome is segmented into two or more parts, and encapsidated in separate
particles that appear to propagate independently. Completing the replication
cycle, however, requires the full genome, so that a systemic infection of a
host requires the concurrent presence of several particles. This represents an
apparent evolutionary drawback of multipartitism, while its advantages remain
unclear. A transition from monopartite to multipartite viral forms has been
described in vitro under conditions of high multiplicity of infection,
suggesting that cooperation between defective mutants is a plausible
evolutionary pathway towards multipartitism. However, it is unknown how the
putative advantages that multipartitism might enjoy at the microscopic level
affect its epidemiology, or if an explicit advantange is needed to explain its
ecological persistence. To disentangle which mechanisms might contribute to the
rise and fixation of multipartitism, we investigate the interaction between
viral spreading dynamics and host population structure. We set up a
compartmental model of the spread of a virus in its different forms and explore
its epidemiology using both analytical and numerical techniques. We uncover
that the impact of host contact structure on spreading dynamics entails a rich
phenomenology of ecological relationships that includes cooperation,
competition, and commensality. We find that multipartitism might rise to
fixation even in the absence of explicit microscopic advantages. Multipartitism
allows the virus to colonize environments that could not be invaded by the
monopartite form, facilitated by homogeneous contacts among hosts. We
conjecture that these features might have led to an increase in the diversity
and prevalence of multipartite viral forms concomitantly with the expansion of
agricultural practices.Comment: 27 pages, 4 figures, 1 tabl
The utility of efavirenz-based prophylaxis against HIV infection. A systems pharmacological analysis
Pre-exposure prophylaxis (PrEP) is considered one of the five “pillars” by UNAIDS to reduce HIV transmission. Moreover, it is a tool for female self-protection against HIV, making it highly relevant to sub-Saharan regions, where women have the highest infection burden. To date, Truvada is the only medication for PrEP. However, the cost of Truvada limits its uptake in resource-constrained countries. Similarly, several currently investigated, patent-protected compounds may be unaffordable in these regions. We set out to explore the potential of the patent-expired antiviral efavirenz (EFV) as a cost-efficient PrEP alternative. A population pharmacokinetic model utilizing data from the ENCORE1 study was developed. The model was refined for metabolic autoinduction. We then explored EFV cellular uptake mechanisms, finding that it is largely determined by plasma protein binding. Next, we predicted the prophylactic efficacy of various EFV dosing schemes after exposure to HIV using a stochastic simulation framework. We predicted that plasma concentrations of 11, 36, 1287 and 1486ng/mL prevent 90% sexual transmissions with wild type and Y181C, K103N and G190S mutants, respectively. Trough concentrations achieved after 600 mg once daily dosing (median: 2017 ng/mL, 95% CI:445–9830) and after reduced dose (400 mg) efavirenz (median: 1349ng/mL, 95% CI: 297–6553) provided complete protection against wild-type virus and the Y181C mutant, and median trough concentrations provided about 90% protection against the K103N and G190S mutants. As reduced dose EFV has a lower toxicity profile, we predicted the reduction in HIV infection when 400 mg EFV-PrEP was poorly adhered to, when it was taken “on demand” and as post-exposure prophylaxis (PEP). Once daily EFV-PrEP provided 99% protection against wild-type virus, if ≥50% of doses were taken. PrEP “on demand” provided complete protection against wild-type virus and prevented ≥81% infections in the mutants. PEP could prevent >98% infection with susceptible virus when initiated within 24 h after virus exposure and continued for at least 9 days. We predict that 400 mg oral EFV may provide superior protection against wild-type HIV. However, further studies are warranted to evaluate EFV as a cost-efficient alternative to Truvada. Predicted prophylactic concentrations may guide release kinetics of EFV long-acting formulations for clinical trial design
Analyzing Machupo virus-receptor binding by molecular dynamics simulations
In many biological applications, we would like to be able to computationally
predict mutational effects on affinity in protein-protein interactions.
However, many commonly used methods to predict these effects perform poorly in
important test cases. In particular, the effects of multiple mutations,
non-alanine substitutions, and flexible loops are difficult to predict with
available tools and protocols. We present here an existing method applied in a
novel way to a new test case; we interrogate affinity differences resulting
from mutations in a host-virus protein-protein interface. We use steered
molecular dynamics (SMD) to computationally pull the machupo virus (MACV) spike
glycoprotein (GP1) away from the human transferrin receptor (hTfR1). We then
approximate affinity using the maximum applied force of separation and the area
under the force-versus-distance curve. We find, even without the rigor and
planning required for free energy calculations, that these quantities can
provide novel biophysical insight into the GP1/hTfR1 interaction. First, with
no prior knowledge of the system we can differentiate among wild type and
mutant complexes. Moreover, we show that this simple SMD scheme correlates well
with relative free energy differences computed via free energy perturbation.
Second, although the static co-crystal structure shows two large
hydrogen-bonding networks in the GP1/hTfR1 interface, our simulations indicate
that one of them may not be important for tight binding. Third, one viral site
known to be critical for infection may mark an important evolutionary
suppressor site for infection-resistant hTfR1 mutants. Finally, our approach
provides a framework to compare the effects of multiple mutations, individually
and jointly, on protein-protein interactions.Comment: 33 pages, 8 figures, 5 table
Transition between immune and disease states in a cellular automaton model of clonal immune response
In this paper we extend the Celada-Seiden (CS) model of the humoral immune
response to include infectious virus and cytotoxic T lymphocytes (cellular
response). The response of the system to virus involves a competition between
the ability of the virus to kill the host cells and the host's ability to
eliminate the virus. We find two basins of attraction in the dynamics of this
system, one is identified with disease and the other with the immune state.
There is also an oscillating state that exists on the border of these two
stable states. Fluctuations in the population of virus or antibody can end the
oscillation and drive the system into one of the stable states. The
introduction of mechanisms of cross-regulation between the two responses can
bias the system towards one of them. We also study a mean field model, based on
coupled maps, to investigate virus-like infections. This simple model
reproduces the attractors for average populations observed in the cellular
automaton. All the dynamical behavior connected to spatial extension is lost,
as is the oscillating feature. Thus the mean field approximation introduced
with coupled maps destroys oscillations.Comment: 27 pages LaTeX + 7 Figures Postscrip
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