  Experiments have shown that hepatitis C virus (HCV) infections in vitro
disseminate both distally via the release and diffusion of cell-free virus
through the medium, and locally via direct, cell-to-cell transmission. To
determine the relative contribution of each mode of infection to HCV
dissemination, we developed an agent-based model (ABM) that explicitly
incorporates both distal and local modes of infection. The ABM tracks the
concentration of extracellular infectious virus in the supernatant and the
number of intracellular HCV RNA segments within each infected cell over the
course of simulated in vitro HCV infections. Experimental data for in vitro HCV
infections conducted in the presence and absence of free-virus neutralizing
antibodies was used to validate the ABM and constrain the value of its
parameters. We found that direct, cell-to-cell infection accounts for 99%
(84%$-$100%, 95% credible interval) of infection events, making it the dominant
mode of HCV dissemination in vitro. Yet, when infection via the free-virus
route is blocked, a 57% reduction in the number of infection events at 72 hpi
is observed experimentally; a result consistent with that found by our ABM.
Taken together, these findings suggest that while HCV spread via cell-free
virus contributes little to the total number of infection events in vitro, it
plays a critical role in enhancing cell-to-cell HCV dissemination by providing
access to distant, uninfected areas, away from the already established large
infection foci.
