Recruitment of apolipoprotein E facilitates Herpes simplex virus 1 release

Over two decades, epidemiological studies have revealed that interactions between human polymorphic apolipoprotein 4 (ApoE, isoform 4) and herpes simplex virus type 1 (HSV1) associate with higher risk of Alzheimer’s disease, a serious and increasing issue among elder populations worldwide. Nevertheless, little is known about the mechanisms behind ApoE-HSV1 interactions at molecular levels. Here, we investigate the effects of ApoE on the HSV1 infectious life cycle in in vitro cell experiments. Analysis of HSV1 growth curves shows that HSV1 production is promoted in presence of any of the three ApoE isoforms, with ApoE 3or 4 demonstrating more efficient pro-viral effects than ApoE 2. When added prior to infection, ApoE inhibits viral attachment but does not affect viral entry. qPCR-based quantification reveals that harbouring ApoE 2, 3, or 4 leads to an increase of HSV1 extracellular release but unchanged levels of viral genome copies within cells or on the cell surface, indicating that virus replication, assembly, or transport to cell membrane are not affected. Further test of virus release directly demonstrates that HSV1 detachment from the cell surface is promoted by ApoE. Subsequent results reveal that ApoE is not only present in purified HSV1 particles produced in ApoE-expressing cells after ultra-centrifugation but also able to incorporate into HSV1 particles after purification, suggesting that harbouring ApoE may promote HSV1 detachment. With the help of total internal reflection microscopy (TIRFM), this hypothesis was tested by quantifying interaction kinetics and apparent affinity between of HSV1 and native supported lipid bilayer. HSV1 particle decorated with ApoE demonstrates higher dissociation rate constants (koff) and less irreversible binding to the membrane, which is in line with the promoted virus release. Similar interaction kinetics have also been tested between non-decorated HSV1 particles and membranes harbouring ApoE but revealed no difference in the kinetics of virus particles on membranes with ApoE present or absent. Overall, our results provide new insights into the roles of ApoE during HSV1 infections, which is worth to be considered when studying their involvement during AD development.