Diffusion-dependent mechanisms of receptor engagement and viral entry

Enveloped viruses attach to host cells by binding to receptors on the cell surface. For many viruses, entry occurs via membrane fusion after a sufficient number of receptors have engaged ligand proteins on the virion. Under conditions where the cell surface receptor densities are low, recruitment of receptors may be limited by diffusion rather than by receptor-ligand interactions. We present a receptor-binding model that includes the effects of receptor availability at the viral binding site. The receptor binding and unbinding kinetics are coupled to receptor diffusion across the cell membrane. We find numerical solutions to our model and analyze the viral entry probabilities and the mean times to entry as functions of receptor concentration, receptor diffusivity, receptor binding stoichiometry, receptor detachment rates, and virus degradation/detachment rates. We also show how entry probabilities and times differ when receptors bind randomly or sequentially to the binding sites on the viral glycoprotein spikes. Our results provide general insight into the biophysical transport mechanisms that may arise in viral attachment and entry.