Hsp90 inhibitor AT-533 blocks HSV-1 nuclear egress and assembly

Abstract Heat shock protein 90 (Hsp90) has been identified as an essential host factor for the infection and replication of several viruses, including HSV-1. Recent works have clearly shown that Hsp90 plays a role in the early stages of HSV-1 infection, including nuclear import and DNA replication. However, the role of Hsp90 in the late stages of HSV-1 infection remains unclear. In this study, we found that Hsp90 was up-regulated during late viral infection. Treatment with the Hsp90 inhibitor AT-533 significantly decreased the intracellular and extracellular virus titers, and strongly inhibited nucleocapsid egress from the nucleus. More detailed studies revealed that AT-533 inhibited the nuclear egress of the viral nucleocapsid by suppressing the expression and translocation of nuclear-associated proteins pUL31 and pUL34. In addition, we found that AT-533 hindered the assembly of virus particles possibly though affecting the localization of glycoproteins in the endoplasmic reticulum and Golgi apparatus. These results thus invoke a new role for Hsp90 in the nucleocapsid egress and viral maturation of HSV-1, and further promote the development of Hsp90 inhibitors as potential anti-HSV-1 drugs.