ترغب بنشر مسار تعليمي؟ اضغط هنا

Quantifying the Sensitivity of HIV-1 Viral Entry to Receptor and Coreceptor Expression

112   0   0.0 ( 0 )
 نشر من قبل Tom Chou
 تاريخ النشر 2018
  مجال البحث علم الأحياء
والبحث باللغة English




اسأل ChatGPT حول البحث

Infection by many viruses begins with fusion of viral and cellular lipid membranes, followed by entry of viral contents into the target cell and ultimately, after many biochemical steps, integration of viral DNA into that of the host cell. The early steps of membrane fusion and viral capsid entry are mediated by adsorption to the cell surface, and receptor and coreceptor binding. HIV-1 specifically targets CD4+ helper T-cells of the human immune system and binds to the receptor CD4 and coreceptor CCR5 before fusion is initiated. Previous experiments have been performed using a cell line (293-Affinofile) in which the expression of CD4 and CCR5 concentration were independently controlled. After exposure to HIV-1 of various strains, the resulting infectivity was measured through the fraction of infected cells. To design and evaluate the effectiveness of drug therapies that target the inhibition of the entry processes, an accurate functional relationship between the CD4/CCR5 concentrations and infectivity is desired in order to more quantitatively analyze experimental data. We propose three kinetic models describing the possible mechanistic processes involved in HIV entry and fit their predictions to infectivity measurements, contrasting and comparing different outcomes. Our approach allows interpretation of the clustering of infectivity of different strains of HIV-1 in the space of mechanistic kinetic parameters. Our model fitting also allows inference of nontrivial stoichiometries of receptor and coreceptor binding and provides a framework through which to quantitatively investigate the effectiveness of fusion inhibitors and neutralizing antibodies.



قيم البحث

اقرأ أيضاً

230 - Sarah A. Nowak , Tom Chou 2008
Enveloped viruses enter host cells either through endocytosis, or by direct fusion of the viral membrane envelope and the membrane of the host cell. However, some viruses, such as HIV-1, HSV-1, and Epstein-Barr can enter a cell through either mechani sm, with the choice of pathway often a function of the ambient physical chemical conditions, such as temperature and pH. We develop a stochastic model that describes the entry process at the level of binding of viral glycoprotein spikes to cell membrane receptors and coreceptors. In our model, receptors attach the cell membrane to the viral membrane, while subsequent binding of coreceptors enables fusion. The model quantifies the competition between fusion and endocytotic entry pathways. Relative probabilities for each pathway are computed numerically, as well as analytically in the high viral spike density limit. We delineate parameter regimes in which fusion or endocytosis is dominant. These parameters are related to measurable and potentially controllable quantities such as membrane bending rigidity and receptor, coreceptor, and viral spike densities. Experimental implications of our mechanistic hypotheses are proposed and discussed.
We study kinetic model of Nuclear Receptor Binding to Promoter Regions. This model is written as a system of ordinary differential equations. Model reduction techniques have been used to simplify chemical kinetics.In this case study, the technique of Pseudo-first order approximation is applied to simplify the reaction rates. CellDesigner has been used to draw the structures of chemical reactions of Nuclear Receptor Binding to Promoter Regions. After model reduction, the general analytical solution for reduced model is given and the number of species and reactions are reduced from 9 species and 6 reactions to 6 species and 5 reactions.
Simulation of biomolecular networks is now indispensable for studying biological systems, from small reaction networks to large ensembles of cells. Here we present a novel approach for stochastic simulation of networks embedded in the dynamic environ ment of the cell and its surroundings. We thus sample trajectories of the stochastic process described by the chemical master equation with time-varying propensities. A comparative analysis shows that existing approaches can either fail dramatically, or else can impose impractical computational burdens due to numerical integration of reaction propensities, especially when cell ensembles are studied. Here we introduce the Extrande method which, given a simulated time course of dynamic network inputs, provides a conditionally exact and several orders-of-magnitude faster simulation solution. The new approach makes it feasible to demonstrate, using decision-making by a large population of quorum sensing bacteria, that robustness to fluctuations from upstream signaling places strong constraints on the design of networks determining cell fate. Our approach has the potential to significantly advance both understanding of molecular systems biology and design of synthetic circuits.
The work reported here aims to address the effects of time-dependent parameters and stochasticity on decision-making in biological systems. We achieve this by extending previous studies that resorted to simple normal forms. Yet, we focus primarily on the issue of the systems sensitivity to initial conditions in the presence of different noise distributions. In addition, we assess the impact of two-way sweeping through the critical region of a canonical Pitchfork bifurcation with a constant external asymmetry. The parallel with decision-making in bio-circuits is performed on this simple system since it is equivalent in its available states and dynamics to more complex genetic circuits. Overall, we verify that rate-dependent effects are specific to particular initial conditions. Information processing for each starting state is affected by the balance between sweeping speed through critical regions, and the type of fluctuations added. For a heavy-tail noise, forward-reverse dynamic bifurcations are more efficient in processing the information contained in external signals, when compared to the system relying on escape dynamics, if it starts at an attractor not favoured by the asymmetry and, in conjunction, if the sweeping amplitude is large.
To shorten the time required to find effective new drugs, like antivirals, a key parameter to consider is membrane permeability, as a compound intended for an intracellular target with poor permeability will have low efficacy. Here, we present a comp utational model that considers both drug characteristics and membrane properties for the rapid assessment of drugs permeability through the coronavirus envelope and various cellular membranes. We analyze 79 drugs that are considered as potential candidates for the treatment of SARS-CoV-2 and determine their time of permeation in different organelle membranes grouped by viral baits and mammalian processes. The computational results are correlated with experimental data, present in the literature, on bioavailability of the drugs, showing a negative correlation between fast permeation and most promising drugs. This model represents an important tool capable of evaluating how permeability affects the ability of compounds to reach both intended and unintended intracellular targets in an accurate and rapid way. The method is general and flexible and can be employed for a variety of molecules, from small drugs to nanoparticles, as well to a variety of biological membranes.
التعليقات
جاري جلب التعليقات جاري جلب التعليقات
سجل دخول لتتمكن من متابعة معايير البحث التي قمت باختيارها
mircosoft-partner

هل ترغب بارسال اشعارات عن اخر التحديثات في شمرا-اكاديميا