Modeling The Endosomal Stage Of Viral Infection

Abstract

Many viruses are endocytosed to enter the cell cytoplasm. To pursue their replication cycle, they have to escape endosome before being digested by lysosomal enzymes. Escape mechanisms are triggered by conformational change of either glycoproteins that deploy a fusogenic activity in the enveloped-viruses case or capsid “penetration” proteins that locally disrupt endosomal membrane in the nude-viruses case. These conformational changes, that can be multistep processes, are linked, directly or not, with endosomal acidification. Moreover, it is increasingly clear that the “fitness” of the escaping virus, that can be the number of bound specific enzymes, is crucial for infection next steps. Consequently, because endocytosed virus must escape in a certain state, before being entirely digested and because escape process, that is a complex chemical process triggered by endosomal acidification, is intrinsically variable and non deterministic, endosomal stage of viral infection calls for quantitative analysis. From biophysical considerations, we present here a general framework to model viral escape and estimate its mean escape time and its corresponding fitness as functions of various parameters such as the the number of viruses and the various rate constants. We apply more specifically the present analysis to the case of the adeno associated virus (AAV), a promising gene carrier in gene delivery.