Markov Chain-Based Stochastic Modelling of HIV-1 Life Cycle in a CD4 T Cell

Mathematics

Igor Sazonov¹  Andreas Meyerhans²  Gennady Bocharov³  Dmitry Grebennikov³ 

[1] College of Engineering, Swansea University, Bay Campus, Fabian Way SA1 8EN, UK;ICREA, Pg. Lluis Companys 23, 08010 Barcelona, Spain;Marchuk Institute of Numerical Mathematics, Russian Academy of Sciences (INM RAS), 119333 Moscow, Russia;

关键词: HIV life cycle;    mathematical model;    stochastic processes;    Markov chain;    heterogeneity;    sensitivity analysis;   

DOI  :  10.3390/math9172025

来源: DOAJ

【 摘 要 】

Replication of Human Immunodeficiency Virus type 1 (HIV) in infected CD4${}^{+}$ T cells represents a key driver of HIV infection. The HIV life cycle is characterised by the heterogeneity of infected cells with respect to multiplicity of infection and the variability in viral progeny. This heterogeneity can result from the phenotypic diversity of infected cells as well as from random effects and fluctuations in the kinetics of biochemical reactions underlying the virus replication cycle. To quantify the contribution of stochastic effects to the variability of HIV life cycle kinetics, we propose a high-resolution mathematical model formulated as a Markov chain jump process. The model is applied to generate the statistical characteristics of the (i) cell infection multiplicity, (ii) cooperative nature of viral replication, and (iii) variability in virus secretion by phenotypically identical cells. We show that the infection with a fixed number of viruses per CD4${}^{+}$ T cell leads to some heterogeneity of infected cells with respect to the number of integrated proviral genomes. The bottleneck factors in the virus production are identified, including the Gag-Pol proteins. Sensitivity analysis enables ranking of the model parameters with respect to the strength of their impact on the size of viral progeny. The first three globally influential parameters are the transport of genomic mRNA to membrane, the tolerance of transcription activation to Tat-mediated regulation, and the degradation of free and mature virions. These can be considered as potential therapeutical targets.

【 授权许可】

Unknown