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Early events in hepatitis B infection: the role of inoculum dose
Authors:Stanca M Ciupe  Naveen K Vaidya  Jonathan E Forde
Institution:1.Department of Mathematics, Virginia Tech, Blacksburg, 24060 VA, USA;2.Department of Mathematics and Statistics, San Diego State University, San Diego, CA 92182, USA;3.Computational Science Research Center, San Diego State University, San Diego, CA 92182, USA;4.Viral Information Institute, San Diego State University, San Diego, CA 92182, USA;5.Department of Mathematics and Computer Science, Hobart and William Smith Colleges, Geneva, New York 14456, USA
Abstract:The relationship between the inoculum dose and the ability of the pathogen to invade the host is poorly understood. Experimental studies in non-human primates infected with different inoculum doses of hepatitis B virus have shown a non-monotonic relationship between dose magnitude and infection outcome, with high and low doses leading to 100% liver infection and intermediate doses leading to less than 0.1% liver infection, corresponding to CD4 T-cell priming. Since hepatitis B clearance is CD8 T-cell mediated, the question of whether the inoculum dose influences CD8 T-cell dynamics arises. To help answer this question, we developed a mathematical model of virus–host interaction following hepatitis B virus infection. Our model explains the experimental data well, and predicts that the inoculum dose affects both the timing of the CD8 T-cell expansion and the quality of its response, especially the non-cytotoxic function. We find that a low-dose challenge leads to slow CD8 T-cell expansion, weak non-cytotoxic functions, and virus persistence; high- and medium-dose challenges lead to fast CD8 T-cell expansion, strong cytotoxic and non-cytotoxic function, and virus clearance; while a super-low-dose challenge leads to delayed CD8 T-cell expansion, strong cytotoxic and non-cytotoxic function, and virus clearance. These results are useful for designing immune cell-based interventions.
Keywords:hepatitis B virus  mathematical models  inoculum dose
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