Abstract
Many aspects of the respiratory syncytial virus (RSV) are still poorly understood. Yet these knowledge gaps have had and could continue to have adverse, unintended consequences for the efficacy and safety of antivirals and vaccines developed against RSV. Mathematical modelling was used to test and evaluate hypotheses about the rate of loss of RSV infectivity and the mechanisms and kinetics of RSV infection spread in SIAT cells in vitro. While the rate of loss of RSV integrity, as measured via qRT-PCR, is well-described by an exponential decay, the latter mechanism failed to describe the rate at which RSV A Long loses infectivity over time in vitro based on the data presented herein. This is unusual given that other viruses (HIV, HCV, influenza) have been shown to lose their infectivity exponentially in vitro, and indeed an exponential rate of loss of infectivity is always assumed in mathematical modelling and experimental analyses. The infectivity profile of RSV in HEp-2 and SIAT cells remained consistent over the course of an RSV infection, over time and a large range of infectivity. However, SIAT cells were found to be ∼ 100× less sensitive to RSV infection than HEp-2 cells. In particular, we found that RSV spreads inefficiently in SIAT cells, in a manner we show is consistent with the establishment of infection resistance in uninfected cells. SIAT cells are a good in vitro model in which to study RSV in vivo dissemination, yielding similar infection timescales. However, the higher sensitivity of HEp-2 cells to RSV together with its RSV infectivity profile being similar to that of SIAT cells, makes HEp-2 cells more suitable for quantifying RSV infectivity over the course of in vitro RSV infections in SIAT cells. Our findings highlight the importance and urgency of resolving the mechanisms at play in the dissemination of RSV infections in vitro, and the processes by which this infectivity is lost.
Highlights
Careful mathematical analysis of viral infection kinetics can provide valuable insight into important features or particularities of a virus which might not be identifiable from the observation of experimental data alone
The total virus concentration refers to the concentration of respiratory syncytial virus (RSV) virions which have retained sufficient genetic integrity to be amplified and quantified via quantitative, real-time, reversetranscription, polymerase chain reaction, providing a measure that is proportional to the concentration of RSV viral RNA
As for the infectious virus concentration, it refers to the concentration of RSV virions which have retained their ability to cause infection, which is quantified using both units of plaque forming units (PFU) in HEp-2 cells and TCID69 in SIAT cells
Summary
Careful mathematical analysis of viral infection kinetics can provide valuable insight into important features or particularities of a virus which might not be identifiable from the observation of experimental data alone. The observed slow progression from HIV infection to AIDS suggests slow cell and virus turnover, yet a mathematical analysis of the plasma viral load decay under antiviral therapy revealed the very rapid kinetics of production matched by an rapid suppression by host immunity [1,2,3,4,5,6]. This finding meant that a very different strategy was required for optimal antiviral therapy, one that takes into consideration the higher likelihood of antiviral resistance emergence brought about by the higher virus production rates than initially believed. The development of safe, reliable and effective anti-RSV vaccine and antiviral therapy would benefit tremendously from a more indepth understanding of the particularities of RSV in terms of what characterizes its infectivity and cell-to-cell dissemination
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