Abstract
Background Developing a quantitative understanding of viral kinetics is useful for determining the pathogenesis and transmissibility of the virus, predicting the course of disease, and evaluating the effects of antiviral therapy. The availability of data in clinical, animal, and cell culture studies, however, has been quite limited. Many studies of virus infection kinetics have been based solely on measures of total or infectious virus count. Here, we introduce a new mathematical model which tracks both infectious and total viral load, as well as the fraction of infected and uninfected cells within a cell culture, and apply it to analyze time-course data of an SHIV infection in vitro. Results We infected HSC-F cells with SHIV-KS661 and measured the concentration of Nef-negative (target) and Nef-positive (infected) HSC-F cells, the total viral load, and the infectious viral load daily for nine days. The experiments were repeated at four different MOIs, and the model was fitted to the full dataset simultaneously. Our analysis allowed us to extract an infected cell half-life of 14.1 h, a half-life of SHIV-KS661 infectiousness of 17.9 h, a virus burst size of 22.1 thousand RNA copies or 0.19 TCID50, and a basic reproductive number of 62.8. Furthermore, we calculated that SHIV-KS661 virus-infected cells produce at least 1 infectious virion for every 350 virions produced. Conclusions Our method, combining in vitro experiments and a mathematical model, provides detailed quantitative insights into the kinetics of the SHIV infection which could be used to significantly improve the understanding of SHIV and HIV-1 pathogenesis. The method could also be applied to other viral infections and used to improve the in vitro determination of the effect and efficacy of antiviral compounds.
Highlights
Developing a quantitative understanding of viral kinetics is useful for determining the pathogenesis and transmissibility of the virus, predicting the course of disease, and evaluating the effects of antiviral therapy
Analyses of experimental data using mathematical models have provided, and continue to provide, quantitative information about the kinetics of viral infections - for human immunodeficiency virus type-1 (HIV-1), the hepatitis C virus (HCV), and the influenza virus - by estimating infection parameters buried within experimental data
Mathematical model To describe the in vitro kinetics of the simian/ human immunodeficiency virus (SHIV)-KS661 viral infection in our experimental system (Table 1), we expanded a basic mathematical model widely used for analyzing viral kinetics [13,17-19,27,38,39]
Summary
Developing a quantitative understanding of viral kinetics is useful for determining the pathogenesis and transmissibility of the virus, predicting the course of disease, and evaluating the effects of antiviral therapy. The study of the highly pathogenic simian/ human immunodeficiency virus (SHIV) has provided important information for the understanding of human immunodeficiency virus type-1 (HIV-1) pathogenesis. It was clarified in an SHIV animal study systemically depletes the CD4+ T cells of rhesus macaques within 4 weeks after infection [6,7]. In observations by our group in recent years, the intravenous infection of rhesus macaques with SHIV-KS661 has consistently resulted in high viremia and CD4+ T cell depletion, followed by malignant morbidity as a result of severe chronic diarrhea and wasting after 6 to 18 months [8] Despite this well-developed in vivo model, the detailed kinetics of SHIV-KS661 remain unclear. Analyses of experimental data using mathematical models have provided, and continue to provide, quantitative information about the kinetics of viral infections - for HIV-1, the hepatitis C virus (HCV), and the influenza virus - by estimating infection parameters buried within experimental data
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