Application of the model to China.

<p>(%) HBV prevalence in the total population, (%) HBV prevalence in children and (%) HDV prevalence in HBV-infected individuals after the introduction of vaccination programs in 1992 in China. Model simulations (lines) and data (markers) obtained from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110143#pone.0110143-Liang1" target="_blank">[25]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110143#pone.0110143-MOHC1" target="_blank">[32]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110143#pone.0110143-Lu1" target="_blank">[34]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110143#pone.0110143-Shen1" target="_blank">[40]</a>.</p

How HBV vertical transmission affects HBV and HDV prevalence in a population.

<p>Equilibrium (%) HBV and (%) HDV prevalence in the total population during HBV mono-infection (solid black line) and dual HBV-HDV epidemics (dotted red line and dashed dotted blue line) relative to: (A) vaccination coverage at HBV perinatal transmission probability ; (B) perinatal transmission rate at 10% vaccination coverage ().</p

Schematic representation of HBV/HDV transmission dynamics in a population.

<p>Schematic representation of HBV/HDV transmission dynamics in a population.</p

Modelling the Impact of Cell-To-Cell Transmission in Hepatitis B Virus

<div><p>Cell-free virus is a well-recognized and efficient mechanism for the spread of hepatitis B virus (HBV) infection in the liver. Cell-to-cell transmission (CCT) can be a more efficient means of virus propagation. Despite experimental evidence implying CCT occurs in HBV, its relative impact is uncertain. We develop a 3-D agent-based model where each hepatocyte changes its viral state according to a dynamical process driven by cell-free virus infection, CCT and intracellular replication. We determine the relative importance of CCT in the development and resolution of acute HBV infection in the presence of cytolytic (CTL) and non-CTL mechanisms. T cell clearance number is defined as the minimum number of infected cells needed to be killed by each T cell at peak infection that results in infection clearance within 12 weeks with hepatocyte turnover (HT, number of equivalent livers) ≤3. We find that CCT has very little impact on the establishment of infection as the mean cccDNA copies/cell remains between 15 to 20 at the peak of the infection regardless of CCT strength. In contrast, CCT inhibit immune-mediated clearance of acute HBV infection as higher CCT strength requires higher T cell clearance number and increases the probability of T cell exhaustion. An effective non-CTL inhibition can counter these negative effects of higher strengths of CCT by supporting rapid, efficient viral clearance and with little liver destruction. This is evident as the T cell clearance number drops by approximately 50% when non-CTL inhibition is increased from 10% to 80%. Higher CCT strength also increases the probability of the incidence of fulminant hepatitis with this phenomenon being unlikely to arise for no CCT. In conclusion, we report the possibility of CCT impacting HBV clearance and its contribution to fulminant hepatitis.</p></div

HBV replication and cell-to-cell transmission.

<p>(A) The HBV life cycle: a HBV DNA virion (<i>V</i>) enters a hepatocyte to deliver rcDNA (<i>R</i>). This is transferred to the nucleus where it is repaired to form cccDNA (<i>C</i>), the template of HBV infection. Transcription of cccDNA produces pgRNA which after reverse transcription forms ssDNA (<i>S</i>) and dsDNA (<i>D</i>). Depending on the level of large surface antigen (<i>P</i>), these dsDNA are either transported back to the nucleus or are exported as new HBV virions. (B) Cell-to-cell transmission between hepatocytes: depending on the level of dsDNA and large surface antigen, infected cells can spread HBV to neighbouring cells. We consider the separate CCT possibilities that an infected cell only transmits infection to uninfected cells or whether it also can increase the rcDNA content in previously infected cells. Transmission to previously infected cells can lead to an increase in cccDNA content.</p

Impact of different antiviral therapies on HBV and HDV prevalence.

<p>(%) HBV and (%) HDV prevalence in the total population relative to time in years for: (A)-(B) IFN therapy reducing HBV infectivity alone in HBV mono-infected, HBV-HDV dually infected individuals and vertical transmission probability when introduced at time in the simulation: (C)-(D) prenylation inhibitor therapy reducing HDV infectivity alone when introduced at time (% efficacy of a treatment is equivalent to the % reduction in infectivity).</p

Parameters, their description and values in model (1) of a single infected cell.

<p>Parameters, their description and values in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161978#pone.0161978.e001" target="_blank">model (1)</a> of a single infected cell.</p

HBV and HDV prevalence under additional preventive measures in China in the next 15 years.

<p>(A) (%) HBV prevalence in the total population, (B) (%) HDV prevalence in the total population, (C) (%) HBV prevalence in children (0–14 years old), and (D) (%) HDV prevalence in HBV infected individuals. Markers were set as for 90% vaccination in children immediately after birth (red dashed line), 100% vaccination in children immediately after birth (blue solid line) and 10% adult vaccination along with 90% vaccination in children immediately after birth (black dashed dotted line).</p

Sensitivity analysis of the parameters representing the rate of children maturing into adulthood and sexual maturity , the HBV vaccination coverage in children immediately after birth , the vertical transmission probability and the rate of partner change on HBV and HDV equilibrium prevalence.

<p>Sensitivity analysis of the parameters representing the rate of children maturing into adulthood and sexual maturity , the HBV vaccination coverage in children immediately after birth , the vertical transmission probability and the rate of partner change on HBV and HDV equilibrium prevalence.</p

Change in the distribution of cccDNA copies/cell with CCT strength.

<p>Distribution of cccDNA copies per cell at day 45 under varying strengths of CCT assuming no cell-to-cell transmission between cells that are already infected, (A) no CCT, (B) weak CCT, (C) moderate CCT, (D) high CCT.</p