Abstract
The hepatitis C virus (HCV) is capable of spreading within a host by two different transmission modes: cell-free and cell-to-cell. However, the contribution of each of these transmission mechanisms to HCV spread is unknown. To dissect the contribution of these different transmission modes to HCV spread, we measured HCV lifecycle kinetics and used an in vitro spread assay to monitor HCV spread kinetics after a low multiplicity of infection in the absence and presence of a neutralizing antibody that blocks cell-free spread. By analyzing these data with a spatially explicit mathematical model that describes viral spread on a single-cell level, we quantified the contribution of cell-free, and cell-to-cell spread to the overall infection dynamics and show that both transmission modes act synergistically to enhance the spread of infection. Thus, the simultaneous occurrence of both transmission modes represents an advantage for HCV that may contribute to viral persistence. Notably, the relative contribution of each viral transmission mode appeared to vary dependent on different experimental conditions and suggests that viral spread is optimized according to the environment. Together, our analyses provide insight into the spread dynamics of HCV and reveal how different transmission modes impact each other.
Highlights
The way a virus spreads within a host is a critical determinant that impacts the establishment and progression of an infection that can affect pathogenesis, host response, and treatment efficacy
We find that for comparable viral diffusion rates as in our experiments (Figure 4E), the relative synergistic effects were largest if ~60%–70% of the infections are due to cell-to-cell transmission (Figure 5B and Figure S7), comparable to the cell-to-cell spread contribution predicted for Exp
While the experimental data demonstrated that infection progressed faster when both transmission modes were available for spread relative to when the cell-free transmission was inhibited by anti-E2 (Figure 2D), our mathematical analysis revealed that the combined spread by cell-free and cell-to-cell transmission results in a synergistic effect that exceeded the additive contribution of both transmission modes (Table 2)
Summary
The way a virus spreads within a host is a critical determinant that impacts the establishment and progression of an infection that can affect pathogenesis, host response, and treatment efficacy. Besides transmission by cell-free viral particles, many viruses [1,2,3], including the hepatitis C virus (HCV) [4,5], have been observed to spread via direct cell-to-cell mechanisms. While diffusing viral particles facilitate the infection of distant cells and transmission to new hosts, direct cell-to-cell transmission between neighboring cells is considered to be more efficient as it can circumvent complex entry processes and shield viral material from neutralizing antibodies [5,6,7]. To which extent these different means of transmission contribute to viral spread and establishment of chronic infection, as well as influence viral escape and disease progression, has not been determined
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