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Understanding Hepatitis B Virus Infection through Hepatocyte Proliferation and Capsid Recycling

Rupchand Sutradhar, D C Dalal

TL;DR

Results of this study suggest that when both hepatocytes proliferate with equal rate, proliferation aids the individual in a rapid recovery from the acute infection whereas in the case of chronic infection, the severity of the infection increases if the proliferation occurs frequently.

Abstract

Proliferation of uninfected as well as infected hepatocytes and recycling of DNA-containing capsids are two major mechanisms playing significant roles in the clearance of hepatitis B virus (HBV) infection. In this study, the temporal dynamics of this infection are investigated through two in silico bio-mathematical models considering both proliferation of hepatocytes and the recycling of capsids. Both models are formulated on the basis of a key finding in the existing literature: mitosis of infected yields in two uninfected progenies. In the first model, we examine regular proliferation (occurs continuously), while the second model deals with the irregular proliferation (happens when the total number of liver cells decreases to less than 70% of its initial volume). The models are calibrated with the experimental data obtained from an adult chimpanzee. Results of this study suggest that when both hepatocytes proliferate with equal rate, proliferation aids the individual in a rapid recovery from the acute infection whereas in the case of chronic infection, the severity of the infection increases if the proliferation occurs frequently. On the other hand, if the infected cells proliferate at a slower rate than uninfected cells, the proliferation of uninfected hepatocytes contributes to increase the infection, but the proliferation of infected hepatocytes acts to reduce the infection from the long-term perspective. Furthermore, it is also observed that the differences between the outcomes of regular and irregular proliferations are substantial and noteworthy.

Understanding Hepatitis B Virus Infection through Hepatocyte Proliferation and Capsid Recycling

TL;DR

Results of this study suggest that when both hepatocytes proliferate with equal rate, proliferation aids the individual in a rapid recovery from the acute infection whereas in the case of chronic infection, the severity of the infection increases if the proliferation occurs frequently.

Abstract

Proliferation of uninfected as well as infected hepatocytes and recycling of DNA-containing capsids are two major mechanisms playing significant roles in the clearance of hepatitis B virus (HBV) infection. In this study, the temporal dynamics of this infection are investigated through two in silico bio-mathematical models considering both proliferation of hepatocytes and the recycling of capsids. Both models are formulated on the basis of a key finding in the existing literature: mitosis of infected yields in two uninfected progenies. In the first model, we examine regular proliferation (occurs continuously), while the second model deals with the irregular proliferation (happens when the total number of liver cells decreases to less than 70% of its initial volume). The models are calibrated with the experimental data obtained from an adult chimpanzee. Results of this study suggest that when both hepatocytes proliferate with equal rate, proliferation aids the individual in a rapid recovery from the acute infection whereas in the case of chronic infection, the severity of the infection increases if the proliferation occurs frequently. On the other hand, if the infected cells proliferate at a slower rate than uninfected cells, the proliferation of uninfected hepatocytes contributes to increase the infection, but the proliferation of infected hepatocytes acts to reduce the infection from the long-term perspective. Furthermore, it is also observed that the differences between the outcomes of regular and irregular proliferations are substantial and noteworthy.
Paper Structure (17 sections, 20 equations, 13 figures, 3 tables)

This paper contains 17 sections, 20 equations, 13 figures, 3 tables.

Table of Contents

  1. Abstract
  2. Introduction
  3. Model formulation and analysis
  4. Parameter estimation and initial condition
  5. Model calibration
  6. Optimal criteria for maintaining smoothly the essential functions of liver
  7. How does the proliferation rate influence the infection?
  8. Effects of same proliferation rates on acute and chronic infection $(r=\rho)$
  9. Steady states
  10. Stability of equilibrium points
  11. Effects of proliferation rate
  12. Effects of different proliferation rates on the infection $(r\neq\rho)$
  13. Acute infection
  14. Chronic infection
  15. Modified model: Proliferation is not a continuous biological process
  16. ...and 2 more sections

Figures (13)

  • Figure 1: Proliferation of an infected hepatocyte results (A): Two uninfected hepatocytes, (B): One uninfected and one infected hepatocytes, (C): Two infected daughter cells. This illustration is created with BioRender.com.
  • Figure 2: Direction field of inequation \ref{['Eqn: of S']}.
  • Figure 3: Comparison of model solution with experimental data. Solid blue line represents model solution whereas red circles reflect the experiment data.
  • Figure 4: Schematic representation of four cases.
  • Figure 5: Convergence of solution to the liver failure equilibrium point for five different initial conditions.
  • ...and 8 more figures

Theorems & Definitions (4)

  • Remark 1
  • Remark 2
  • Remark 3
  • Remark 4