Mechanisms of receptor/coreceptor-mediated entry of enveloped viruses

TL;DR

This paper presents a stochastic model for enveloped virus entry into host cells, analyzing how receptor and coreceptor interactions influence the choice between fusion and endocytosis pathways under various physical conditions.

Contribution

It introduces a novel stochastic modeling approach that quantifies the competition between fusion and endocytosis during viral entry, linking it to measurable physical parameters.

Findings

Identifies parameter regimes favoring fusion or endocytosis.

Provides analytical and numerical estimates of pathway probabilities.

Suggests experimental tests for mechanistic hypotheses.

Abstract

Enveloped viruses enter host cells either through endocytosis, or by direct fusion of the viral membrane envelope and the membrane of the host cell. However, some viruses, such as HIV-1, HSV-1, and Epstein-Barr can enter a cell through either mechanism, with the choice of pathway often a function of the ambient physical chemical conditions, such as temperature and pH. We develop a stochastic model that describes the entry process at the level of binding of viral glycoprotein spikes to cell membrane receptors and coreceptors. In our model, receptors attach the cell membrane to the viral membrane, while subsequent binding of coreceptors enables fusion. The model quantifies the competition between fusion and endocytotic entry pathways. Relative probabilities for each pathway are computed numerically, as well as analytically in the high viral spike density limit. We delineate parameter regimes in which fusion or endocytosis is dominant. These parameters are related to measurable and potentially controllable quantities such as membrane bending rigidity and receptor, coreceptor, and viral spike densities. Experimental implications of our mechanistic hypotheses are proposed and discussed.