Virus Entry via Endocytic Pathways

Numerous viruses depend on the host cell's endocytic machinery for entry and productive infection. The endocytic pathways utilized include caveolar-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis. In order to enter the host cells, viruses must first bind to the cell surface using attachment factors (E.g. ceramide, ganglioside, sialic acid) or virus receptors (E.g. CAR, DAF, integrins). The interaction between viruses and the attachment factors are relatively nonspecific and help to concentrate viruses on the host cell surface. Unlike attachment factors, virus receptors actively promote viral entry by activating signaling pathways that promote endocytosis of the virus.Caveolar-mediated endocytosis is a cholesterol-dependent pathway that internalizes viruses including simian virus 40, polyoma virus, filoviruses such as Ebola and Marburg, and Coxsackie virus. The interaction between the virus and the receptor triggers formation of caveolae around the viral particles which transport the virus to the caveosomes and then to the endoplasmic reticulum or the perinuclear region.Clathrin-coated endocytosis is the most commonly used route for viruses such as influenza virus, adenovirus, vesicular stomatitis virus, hepatitis C and parechovirus type 1. The initial binding between the virus and the receptor on the cell surface activates signaling pathways, which lead to the formation of clathrin-coated vesicles. Numerous adaptors, cofactors and tethering proteins are involved in the formation of the clathrin-coated pits and vesicles, demonstrating the complexity of this endocytic pathway. The clathrin-coated vesicles deliver the virus to endosomes and eventually to lysosomes.Macropinocytosis is a non-specific mechanism for internalization, and not many viruses are known to use this process for host cell entry and infection. Macropinocytosis is dependent on the activation of PI3K and Rho family small GTPases, which regulate actin polymerization, leading to membrane ruffling and formation of large, irregular vesicles known as macropinosomes. It seems that vaccinia virus, which is too large to enter clathrin-coated pits, uses macropinocytosis to infect host cells. Moreover, following binding to CAR and αV integrin receptors, adenovirus stimulates macropinocytosis not for viral uptake but to enhance viral penetration from endosome. The adenovirus entry itself occurs via clathrin-mediated endocytosis.