Development of Novel Antivirals

An understanding of viral entry mechanisms is critical for the effective design and development of compounds to prevent viral infection.

We have a longstanding interest in defining the mechanisms by which HSV-2 enters host cells. These efforts have identified a novel mechanism of viral entry (diagrammed above), where binding of glycoprotein C (gC) or gB of HSV-2 an the engagement of nectin-1 by gD triggers the release of small amounts of calcium ions near the host cell plasma membrane. While small, this calcium release is sufficient to activate phospholipid scramblase, resulting in the translocation of phosphatidylserines from the inner to the outer leaflet of the plasma membrane. This translocation also results in the externalization of the kinase Akt, which then interacts with gB of HSV-2, which promotes the activation of Akt. Activated Akt, together with integrin αvβ3 activated by interactions with gH, sends signals that culminate in the release of large calcium stores. This calcium release promotes the fusion of the viral envelope and plasma membrane, and the entry of viral capsids into the host cell.

Ongoing work aims to expand these studies into other cell types, other viruses, and other biological phenomena.