Apolipoprotein E and Viral Infection: Risks and Mechanisms

Apolipoprotein E (ApoE) is a multifunctional protein critical for lipid metabolism and cholesterol homeostasis. In addition to being a well known genetic determinant of both neurodegenerative and cardiovascular diseases, ApoE is frequently involved in various viral infection-related diseases. Human ApoE protein is functionally polymorphic with three isoforms, namely, ApoE2, ApoE3, and ApoE4, with markedly altered protein structures and functions. ApoE4 is associated with increased susceptibility to infection with herpes simplex virus type-1 and HIV. Conversely, ApoE4 protects against hepatitis C virus and hepatitis B virus infection. With the outbreak of coronavirus disease 2019, ApoE4 has been shown to determine the incidence and progression of severe acute respiratory syndrome coronavirus 2 infection. These findings clearly indicate the critical role of ApoE in viral infection. Furthermore, ApoE polymorphism has various or even opposite effects in these infection processes, which are partly related to the structural features that distinguish the different ApoE statuses. In the current review, we summarize the emerging relationship between ApoE and viral infection, discuss the potential mechanisms, and identify future directions that may help to advance our understanding of the link between ApoE and viral infection.