Evolutionary non-linear modelling for selecting vaccines against antigenically variable viruses
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Abstract Motivation: In vitro and in vivo selection of vaccines is time consuming, expensive and the selected vaccines may not be able to provide protection against broad-spectrum viruses because of emerging antigenically novel disease strains. A powerful computational model that incorporates these protein/DNA or RNA level fluctuations can effectively predict antigenically variant strains, and can minimize the amount of resources spent on exclusive serological testing of vaccines and make wide spectrum vaccines possible for many diseases. However, in silico vaccine prediction remains a grand challenge. To address the challenge, we investigate the use of linear and non-linear regression models to predict the antigenic similarity in foot-and-mouth disease virus strains and in influenza strains, where the structure and parameters of the non-linear model are optimized using an evolutionary algorithm (EA). In addition, we examine two different scoring methods for weighting the type of amino acid substitutions in the linear and non-linear models. We also test our models with some unseen data. Results: We achieved the best prediction results on three datasets of SAT2 (Foot-and-Mouth disease), two datasets of serotype A (Foot-and-Mouth disease) and two datasets of influenza when the scoring method based on biochemical properties of amino acids is employed in combination with a non-linear regression model. Models based on substitutions in the antigenic areas performed better than those that took the entire exposed viral capsid proteins. A majority of the non-linear regression models optimized with the EA performed better than the linear and non-linear models whose parameters are estimated using the least-squares method. In addition, for the best models, optimized non-linear regression models consist of more terms than their linear counterparts, implying a non-linear nature of influences of amino acid substitutions. Our models were also tested on five recently generated FMDV datasets and the best model was able to achieve an 80% agreement rate. Contact: yaochu.jin@surrey.ac.uk or e.laing@surrey.ac.ukKeywords:
Lasso
Similarity (geometry)
Strain (injury)
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The foot-and-mouth disease virus (FMDV) structural protein precursor, P1-2A, is cleaved by the virus-encoded 3C protease (3C(pro)) into the capsid proteins VP0, VP1 and VP3 (and 2A). In some systems, it is difficult to produce large amounts of these processed capsid proteins since 3C(pro) can be toxic for cells. The expression level of 3C(pro) activity has now been reduced relative to the P1-2A, and the effect on the yield of processed capsid proteins and their assembly into empty capsid particles within mammalian cells has been determined. Using a vaccinia-virus-based transient expression system, P1-2A (from serotypes O and A) and 3C(pro) were expressed from monocistronic cDNA cassettes as P1-2A-3C, or from dicistronic cassettes with the 3C(pro) expression dependent on a mutant FMDV internal ribosome entry site (IRES) (designated P1-2A-mIRES-3C). The effects of using a mutant 3C(pro) with reduced catalytic activity or using two different mutant IRES elements (the wt GNRA tetraloop sequence GCGA converted, in the cDNA, to GAGA or GTTA) were analysed. For both serotypes, the P1-2A-mIRES-3C construct containing the inefficient GTTA mutant IRES produced the highest amount of processed capsid proteins. These products self-assembled to form FMDV empty capsid particles, which have a related, but distinct, morphology (as determined by electron microscopy and reconstruction) from that determined previously by X-ray crystallography. The assembled empty capsids bind, in a divalent cation-dependent manner, to the RGD-dependent integrin αvβ6, a cellular receptor for FMDV, and are recognized appropriately in serotype-specific antigen ELISAs.
Picornavirus
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Single-stranded genomes of adeno-associated virus (AAV) are packaged into preformed capsids. It has been proposed that packaging is initiated by interaction of genome-bound Rep proteins to the capsid, thereby targeting the genome to the portal of encapsidation. Here we describe a panel of mutants with amino acid exchanges in the pores at the fivefold axes of symmetry on AAV2 capsids with reduced packaging and reduced Rep-capsid interaction. Mutation of two threonines at the rim of the fivefold pore nearly completely abolished Rep-capsid interaction and packaging. This suggests a Rep-binding site at the highly conserved amino acids at or close to the pores formed by the capsid protein pentamers. A different mutant (P. Wu, W. Xiao, T. Conlon, J. Hughes, M. Agbandje-McKenna, T. Ferkol, T. Flotte, and N. Muzyczka, J. Virol. 74:8635-8647, 2000) with an amino acid exchange at the interface of capsid protein pentamers led to a complete block of DNA encapsidation. Analysis of the capsid conformation of this mutant revealed that the pores at the fivefold axes were occupied by VP1/VP2 N termini, thereby preventing DNA introduction into the capsid. Nevertheless, the corresponding capsids had more Rep proteins bound than wild-type AAV, showing that correct Rep interaction with the capsid depends on a defined capsid conformation. Both mutant types together support the conclusion that the pores at the fivefold symmetry axes are involved in genome packaging and that capsid conformation-dependent Rep-capsid interactions play an essential role in the packaging process.
Capsomere
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Capsomere
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Capsomere
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Lasso
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Stepwise regression
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Capsomere
Cryo-Electron Microscopy
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To construct the recombinant baculovirus expressing capsid proteins of serotype O foot-and-mouth disease virus(FMDV),a fusion gene of P1-2A and 3C of FMDV O/YS/CHA/05 strain was expressed from the constructed recombinant baculovirus rBV-P12A3C in Sf9 cells detected by indirect immunefluorescence assay.Western blot analyses showed that the expressed capsid protein was correctly cleavage by 3C proteinase.In addition,expression kinetics analysis showed that the expressed FMDV capsid proteins possessed good reactogenicity and the maximal expression of the capsid proteins in Sf9 cells occurred at the 4th day post infection with the recombinant baculovirus.The construction of the recombinant baculovirus would help to study the assembly of FMDV empty capsids in vitro and develop the serotype O FMDV empty capsid vaccine.
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The linear model of the regression function is a widely used and perhaps, in most cases, highly unrealistic simplifying assumption, when proposing consistent variable selection methods for large and highly-dimensional datasets. In this paper, we study what happens from theoretical point of view, when a variable selection method assumes a linear regression function and the underlying ground-truth model is composed of a linear and a non-linear term, that is at most partially linear. We demonstrate consistency of the Lasso method when the model is partially linear. However, we note that the algorithm tends to increase even more the number of selected false positives on partially linear models when given few training samples. That is usually because the values of small groups of samples happen to explain variation coming from the non-linear part of the response function and the noise, using a linear combination of wrong predictors. We demonstrate theoretically that false positives are likely to be selected by the Lasso method due to a small proportion of samples, which happen to explain some variation in the response variable. We show that this property implies that if we run the Lasso on several slightly smaller size data replications, sampled without replacement, and intersect the results, we are likely to reduce the number of false positives without losing already selected true positives. We propose a novel consistent variable selection algorithm based on this property and we show it can outperform other variable selection methods on synthetic datasets of linear and partially linear models and datasets from the UCI machine learning repository.
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Elastic net regularization
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This review summarized the molecular determinants of the acid stability of FMDV in order to explore the uncoating mechanism of FMDV and improve the acid stability of vaccines. The foot-and-mouth disease virus (FMDV) capsid is highly acid labile and tends to dissociate into pentameric subunits at acidic condition to release viral RNA for initiating virus replication. However, the acid stability of virus capsid is greatly required for the maintenance of intact virion during the process of virus culture and vaccine production. The conflict between the acid lability in vivo and acid stability in vitro of FMDV capsid promotes the selection of a series of amino acid substitutions which can confer resistance to acid-induced FMDV inactivation. In order to explore the uncoating activity of FMDV and enhance the acid stability of vaccines, we summarized the available works about the pH stability of FMDV. In this review, we analyzed the intrinsic reasons for the acid instability of FMDV from the structural and functional aspects. We also listed all substitutions obtained by different research methods and showed them in the partial capsid of FMDV. We found that a quadrangle region in the viral capsid was the place where a great many pH-sensitive residues were distributed. As the uncoating event of FMDV is dependent on the pH-sensitive amino acid residues in the capsid, this most pH-sensitive position indicates a potential candidate location for RNA delivery triggered by the acid-induced coat disassociation. This review provided an overview of the pH stability of FMDV. The study of pH stability of FMDV not only contributes to the exploration of molecule and mechanism information for FMDV uncoating, but also enlightens the development of FMDV vaccines, including the traditionally inactivated vaccines and the new VLP (virus-like particle) vaccines.
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