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Dendritic cells (DCs) are the most effective professional antigen-presenting cell. They ferry antigen from the extremities to T cells and are essential for the initiation of an adaptive immune response. Despite interest in how DCs respond to chemical stimuli, there have been few attempts to model DC migration. In this paper, we simulate the motility of DCs by modeling the generation of forces by filopodia and a force balance on the cell. The direction of fliopodial extension is coupled to differential occupancy of cognate chemokine receptors across the cell. Our model simulates chemokinesis and chemotaxis in a variety of chemical and mechanical environments. Simulated DCs undergoing chemokinesis were measured to have a speed of 5.1 ± 0.07 μm·min-1 and a persistence time of 3.2 ± 0.46 min, consistent with experiment. Cells undergoing chemotaxis exhibited a stronger chemotactic response when exposed to lower average chemokine concentrations, also consistent with experiment. We predicted that when placed in two opposing gradients, cells will cluster in a line, which we call the “line of equistimulation;” this clustering has also been observed. We calculated the effect of varying gradient steepness on the line of equistimulation, with steeper gradients resulting in tighter clustering. Moreover, gradients are found to be most potent when cells are in a gradient of chemokine whose mean concentration is close to the binding of the Kd to the receptor, and least potent when the mean concentration is 0.1Kd. Comparing our simulations to experiment, we can give a quantitative measure of the strength of certain chemokines relative to others. Assigning the signal of CCL19 binding CCR7 a baseline strength of 1, we found CCL21 binding CCR7 had a strength of 0.28, and CXCL12 binding CXCR4 had a strength of 0.30. These differences emerge despite both chemokines having virtually the same Kd, suggesting a mechanism of signal amplification in DCs requiring further study. [ABSTRACT FROM AUTHOR]

Prophylactic interventions such as vaccine allocation are some of the most effective public health policy planning tools. The supply of vaccines, however, is limited and an important challenge is to optimally allocate the vaccines to minimize epidemic impact. This resource allocation question (which we refer to as VID) has multiple dimensions: when, where, to whom, etc. Most of the existing literature in this topic deals with the latter (to whom), proposing policies that prioritize individuals by age and disease risk. However, since seasonal influenza spread has a typical spatial trend, and due to the temporal constraints enforced by the availability schedule, the when and where problems become equally, if not more, relevant. In this paper, we study the VID problem in the context of seasonal influenza spread in the United States. We develop a national scale metapopulation model for influenza that integrates both short and long distance human mobility, along with realistic data on vaccine uptake. We also design GA, a greedy algorithm for allocating the vaccine supply at the state level under temporal constraints and show that such a strategy improves over the current baseline of pro-rata allocation, and the improvement is more pronounced for higher vaccine efficacy and moderate flu season intensity. Further, the resulting strategy resembles a ring vaccination applied spatiallyacross the US. [ABSTRACT FROM AUTHOR]

The collection of immunoglobulin genes in an individual’s germline, which gives rise to B cell receptors via recombination, is known to vary significantly across individuals. In humans, for example, each individual has only a fraction of the several hundred known V alleles. Furthermore, the currently-accepted set of known V alleles is both incomplete (particularly for non-European samples), and contains a significant number of spurious alleles. The resulting uncertainty as to which immunoglobulin alleles are present in any given sample results in inaccurate B cell receptor sequence annotations, and in particular inaccurate inferred naive ancestors. In this paper we first show that the currently widespread practice of aligning each sequence to its closest match in the full set of IMGT alleles results in a very large number of spurious alleles that are not in the sample’s true set of germline V alleles. We then describe a new method for inferring each individual’s germline gene set from deep sequencing data, and show that it improves upon existing methods by making a detailed comparison on a variety of simulated and real data samples. This new method has been integrated into the partis annotation and clonal family inference package, available at , and is run by default without affecting overall run time. [ABSTRACT FROM AUTHOR]

B cells develop high affinity receptors during the course of affinity maturation, a cyclic process of mutation and selection. At the end of affinity maturation, a number of cells sharing the same ancestor (i.e. in the same “clonal family”) are released from the germinal center; their amino acid frequency profile reflects the allowed and disallowed substitutions at each position. These clonal-family-specific frequency profiles, called “substitution profiles”, are useful for studying the course of affinity maturation as well as for antibody engineering purposes. However, most often only a single sequence is recovered from each clonal family in a sequencing experiment, making it impossible to construct a clonal-family-specific substitution profile. Given the public release of many high-quality large B cell receptor datasets, one may ask whether it is possible to use such data in a prediction model for clonal-family-specific substitution profiles. In this paper, we present the method “Substitution Profiles Using Related Families” (SPURF), a penalized tensor regression framework that integrates information from a rich assemblage of datasets to predict the clonal-family-specific substitution profile for any single input sequence. Using this framework, we show that substitution profiles from similar clonal families can be leveraged together with simulated substitution profiles and germline gene sequence information to improve prediction. We fit this model on a large public dataset and validate the robustness of our approach on two external datasets. Furthermore, we provide a command-line tool in an open-source software package () implementing these ideas and providing easy prediction using our pre-fit models. [ABSTRACT FROM AUTHOR]

Viral infections are one of the major causes of death worldwide, with HIV infection alone resulting in over 1.2 million casualties per year. Antiviral drugs are now being administered for a variety of viral infections, including HIV, hepatitis B and C, and influenza. These therapies target a specific phase of the virus’s life cycle, yet their ultimate success depends on a variety of factors, such as adherence to a prescribed regimen and the emergence of viral drug resistance. The epidemiology and evolution of drug resistance have been extensively characterized, and it is generally assumed that drug resistance arises from mutations that alter the virus’s susceptibility to the direct action of the drug. In this paper, we consider the possibility that a virus population can evolve towards synchronizing its life cycle with the pattern of drug therapy. The periodicity of the drug treatment could then allow for a virus strain whose life cycle length is a multiple of the dosing interval to replicate only when the concentration of the drug is lowest. This process, referred to as “drug tolerance by synchronization”, could allow the virus population to maximize its overall fitness without having to alter drug binding or complete its life cycle in the drug’s presence. We use mathematical models and stochastic simulations to show that life cycle synchronization can indeed be a mechanism of viral drug tolerance. We show that this effect is more likely to occur when the variability in both viral life cycle and drug dose timing are low. More generally, we find that in the presence of periodic drug levels, time-averaged calculations of viral fitness do not accurately predict drug levels needed to eradicate infection, even if there is no synchronization. We derive an analytical expression for viral fitness that is sufficient to explain the drug-pattern-dependent survival of strains with any life cycle length. We discuss the implications of these findings for clinically relevant antiviral strategies. [ABSTRACT FROM AUTHOR]

Genetic risk prediction is an important goal in human genetics research and precision medicine. Accurate prediction models will have great impacts on both disease prevention and early treatment strategies. Despite the identification of thousands of disease-associated genetic variants through genome wide association studies (GWAS), genetic risk prediction accuracy remains moderate for most diseases, which is largely due to the challenges in both identifying all the functionally relevant variants and accurately estimating their effect sizes in the presence of linkage disequilibrium. In this paper, we introduce AnnoPred, a principled framework that leverages diverse types of genomic and epigenomic functional annotations in genetic risk prediction for complex diseases. AnnoPred is trained using GWAS summary statistics in a Bayesian framework in which we explicitly model various functional annotations and allow for linkage disequilibrium estimated from reference genotype data. Compared with state-of-the-art risk prediction methods, AnnoPred achieves consistently improved prediction accuracy in both extensive simulations and real data. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have identified tens of thousands of genetic variants associated with hundreds of phenotypes and diseases, which have provided clinical and medical benefits to patients with novel biomarkers and therapeutic targets. However, identification of risk variants associated with complex diseases remains challenging as they are often affected by many genetic variants with small or moderate effects. There has been accumulating evidence suggesting that different complex traits share common risk basis, namely pleiotropy. Recently, several statistical methods have been developed to improve statistical power to identify risk variants for complex traits through a joint analysis of multiple GWAS datasets by leveraging pleiotropy. While these methods were shown to improve statistical power for association mapping compared to separate analyses, they are still limited in the number of phenotypes that can be integrated. In order to address this challenge, in this paper, we propose a novel statistical framework, graph-GPA, to integrate a large number of GWAS datasets for multiple phenotypes using a hidden Markov random field approach. Application of graph-GPA to a joint analysis of GWAS datasets for 12 phenotypes shows that graph-GPA improves statistical power to identify risk variants compared to statistical methods based on smaller number of GWAS datasets. In addition, graph-GPA also promotes better understanding of genetic mechanisms shared among phenotypes, which can potentially be useful for the development of improved diagnosis and therapeutics. The R implementation of graph-GPA is currently available at . [ABSTRACT FROM AUTHOR]

Ancestral state reconstruction in Bayesian phylogeography of virus pandemics have been improved by utilizing a Bayesian stochastic search variable selection (BSSVS) framework. Recently, this framework has been extended to model the transition rate matrix between discrete states as a generalized linear model (GLM) of genetic, geographic, demographic, and environmental predictors of interest to the virus and incorporating BSSVS to estimate the posterior inclusion probabilities of each predictor. Although the latter appears to enhance the biological validity of ancestral state reconstruction, there has yet to be a comparison of phylogenies created by the two methods. In this paper, we compare these two methods, while also using a primitive method without BSSVS, and highlight the differences in phylogenies created by each. We test six coalescent priors and six random sequence samples of H3N2 influenza during the 2014–15 flu season in the U.S. We show that the GLMs yield significantly greater root state posterior probabilities than the two alternative methods under five of the six priors, and significantly greater Kullback-Leibler divergence values than the two alternative methods under all priors. Furthermore, the GLMs strongly implicate temperature and precipitation as driving forces of this flu season and nearly unanimously identified a single root state, which exhibits the most tropical climate during a typical flu season in the U.S. The GLM, however, appears to be highly susceptible to sampling bias compared with the other methods, which casts doubt on whether its reconstructions should be favored over those created by alternate methods. We report that a BSSVS approach with a Poisson prior demonstrates less bias toward sample size under certain conditions than the GLMs or primitive models, and believe that the connection between reconstruction method and sampling bias warrants further investigation. [ABSTRACT FROM AUTHOR]

The human immune system depends on a highly diverse collection of antibody-making B cells. B cell receptor sequence diversity is generated by a random recombination process called “rearrangement” forming progenitor B cells, then a Darwinian process of lineage diversification and selection called “affinity maturation.” The resulting receptors can be sequenced in high throughput for research and diagnostics. Such a collection of sequences contains a mixture of various lineages, each of which may be quite numerous, or may consist of only a single member. As a step to understanding the process and result of this diversification, one may wish to reconstruct lineage membership, i.e. to cluster sampled sequences according to which came from the same rearrangement events. We call this clustering problem “clonal family inference.” In this paper we describe and validate a likelihood-based framework for clonal family inference based on a multi-hidden Markov Model (multi-HMM) framework for B cell receptor sequences. We describe an agglomerative algorithm to find a maximum likelihood clustering, two approximate algorithms with various trade-offs of speed versus accuracy, and a third, fast algorithm for finding specific lineages. We show that under simulation these algorithms greatly improve upon existing clonal family inference methods, and that they also give significantly different clusters than previous methods when applied to two real data sets. [ABSTRACT FROM AUTHOR]

In this paper we introduce a fully flexible coarse-grained model of immunoglobulin G (IgG) antibodies parametrized directly on cryo-EM data and simulate the binding dynamics of many IgGs to antigens adsorbed on a surface at increasing densities. Moreover, we work out a theoretical model that allows to explain all the features observed in the simulations. Our combined computational and theoretical framework is in excellent agreement with surface-plasmon resonance data and allows us to establish a number of important results. (i) Internal flexibility is key to maximize bivalent binding, flexible IgGs being able to explore the surface with their second arm in search for an available hapten. This is made clear by the strongly reduced ability to bind with both arms displayed by artificial IgGs designed to rigidly keep a prescribed shape. (ii) The large size of IgGs is instrumental to keep neighboring molecules at a certain distance (surface repulsion), which essentially makes antigens within reach of the second Fab always unoccupied on average. (iii) One needs to account independently for the thermodynamic and geometric factors that regulate the binding equilibrium. The key geometrical parameters, besides excluded-volume repulsion, describe the screening of free haptens by neighboring bound antibodies. We prove that the thermodynamic parameters govern the low-antigen-concentration regime, while the surface screening and repulsion only affect the binding at high hapten densities. Importantly, we prove that screening effects are concealed in relative measures, such as the fraction of bivalently bound antibodies. Overall, our model provides a valuable, accurate theoretical paradigm beyond existing frameworks to interpret experimental profiles of antibodies binding to multi-valent surfaces of different sorts in many contexts. [ABSTRACT FROM AUTHOR]

During early human immunodeficiency virus (HIV) infection multiple CD8+ T cell responses are elicited almost simultaneously. These responses exert strong selective pressures on different parts of HIV’s genome, and select for mutations that escape recognition and are thus beneficial to the virus. Some studies reveal that the later these escape mutations emerge, the more slowly they go to fixation. This pattern of escape rate decrease(ERD) can arise by distinct mechanisms. In particular, in large populations with high beneficial mutation rates interference among different escape strains –an effect that can emerge in evolution with asexual reproduction and results in delayed fixation times of beneficial mutations compared to sexual reproduction– could significantly impact the escape rates of mutations. In this paper, we investigated how interference between these concurrent escape mutations affects their escape rates in systems with multiple epitopes, and whether it could be a source of the ERD pattern. To address these issues, we developed a multilocus Wright-Fisher model of HIV dynamics with selection, mutation and recombination, serving as a null-model for interference. We also derived an interference-free null model assuming initial neutral evolution before immune response elicitation. We found that interference between several equally selectively advantageous mutations can generate the observed ERD pattern. We also found that the number of loci, as well as recombination rates substantially affect ERD. These effects can be explained by the underexponential decline of escape rates over time. Lastly, we found that the observed ERD pattern in HIV infected individuals is consistent with both independent, interference-free mutations as well as interference effects. Our results confirm that interference effects should be considered when analyzing HIV escape mutations. The challenge in estimating escape rates and mutation-associated selective coefficients posed by interference effects cannot simply be overcome by improved sampling frequencies or sizes. This problem is a consequence of the fundamental shortcomings of current estimation techniques under interference regimes. Hence, accounting for the stochastic nature of competition between mutations demands novel estimation methodologies based on the analysis of HIV strains, rather than mutation frequencies. [ABSTRACT FROM AUTHOR]