No abstract

Virus density distribution as a function of genotype considered as a continuous variable and of time is studied with a nonlocal reaction-diffusion equation taking into account virus competition for the host cells and its elimination by the immune response and by the genotype-dependent mortality. The existence of virus strains, that is, of positive stable stationary solutions decaying at infinity, is determined by the admissible intervals in the genotype space where the genotype-dependent mortality is less than the virus reproduction rate, and by the immune response under some appropriate assumptions on the immune response function characterizing virus elimination by immune cells. The competition of virus strains is studied, first, without immune response and then with the immune response. In the absence of immune response, the strain dynamics is different in a short time scale where they converge to some intermediate slowly evolving solutions depending on the initial conditions, and in a long time scale where their distribution converges to a stationary solution. Immune response can essentially influence the strain dynamics either stabilizing them or eliminating one of the strains. An antiviral treatment can also influence the competition of virus strains, and it can lead to the emergence of resistant strains, which were absent before the treatment because of the competition with susceptible strains.Communicated by Francesco dell'Isola. MSC2010: 35K57, 92C30.

In this work, we develop mathematical models of the immune response to respiratory viral infection, taking into account some particular properties of the SARS-CoV infections, cytokine storm and vaccination. Each model consists of a system of ordinary differential equations that describe the interactions of the virus, epithelial cells, immune cells, cytokines, and antibodies. Conventional analysis of the existence and stability of stationary points is completed by numerical simulations in order to study the dynamics of solutions. The behavior of the solutions is characterized by large peaks of virus concentration specific to acute respiratory viral infections. At the first stage, we study the innate immune response based on the protective properties of interferon secreted by virus-infected cells. Viral infection down-regulates interferon production. This competition can lead to the bistability of the system with different regimes of infection progression with high or low intensity. After that, we introduce the adaptive immune response with antigen-specific T- and B-lymphocytes. The resulting model shows how the incubation period and the maximal viral load depend on the initial viral load and the parameters of the immune response. In particular, an increase in the initial viral load leads to a shorter incubation period and higher maximal viral load. The model shows that a deficient production of antibodies leads to an increase in the incubation period and even higher maximum viral loads. In order to study the emergence and dynamics of cytokine storm, we consider proinflammatory cytokines produced by cells of the innate immune response. Depending on the parameters of the model, the system can remain in the normal inflammatory state specific for viral infections or, due to positive feedback between inflammation and immune cells, pass to cytokine storm characterized by the excessive production of proinflammatory cytokines. Finally, we study the production of antibodies due to vaccination. We determine the dose–response dependence and the optimal interval of vaccine dose. Assumptions of the model and obtained results correspond to the experimental and clinical data.

Ключевые слова: врожденный иммунный ответ, цитокиновый шторм, математическое моделирование Работа выполнена при финансовой поддержке Министерства науки и высшего образования Российской Федерации в рамках государственного задания: соглашение № 075-03-2020-223/3 (FSSF-2020-0018). Авторы выражают благодарность анонимным рецензентам за их ценные комментарии.