Vaccinia virus has a broad range of infectivity in many cell lines and animals. Although it is known that the
vaccinia mature virus binds to cell surface
glycosaminoglycans and
extracellular matrix proteins, whether additional cellular receptors are required for virus entry remains unclear. Our previous studies showed that the
vaccinia mature virus enters through
lipid rafts, suggesting the involvement of raft-associated cellular
proteins. Here we demonstrate that one
lipid raft-associated
protein,
integrin β1, is important for
vaccinia mature virus entry into HeLa cells. Vaccinia virus associates with
integrin β1 in
lipid rafts on the cell surface, and the knockdown of
integrin β1 in HeLa cells reduces
vaccinia mature virus entry. Additionally,
vaccinia mature
virus infection is reduced in a mouse cell line, GD25, that is deficient in
integrin β1 expression.
Vaccinia mature
virus infection triggers the activation of
phosphatidylinositol 3-kinase (PI3K)/Akt signaling, and the treatment of cells with inhibitors to block P13K activation reduces virus entry in an
integrin β1-dependent manner, suggesting that
integrin β1-mediates PI3K/Akt activation induced by vaccinia virus and that this signaling pathway is essential for virus endocytosis. The inhibition of
integrin β1-mediated cell adhesion results in a reduction of vaccinia virus entry and the disruption of focal adhesion and PI3K/Akt activation. In summary, our results show that the binding of
vaccinia mature virus to cells mimics the outside-in activation process of
integrin functions to facilitate vaccinia virus entry into HeLa cells.