National Institute of Allergy and Infectious Diseases 5R01AI170834-04

Targeting Nuclear HSF1 as a Novel Anti-HCMV Strategy

The award funds research to develop a novel therapeutic strategy targeting heat shock factor 1 (HSF1) to combat human cytomegalovirus (HCMV) infection and latency. The project explores the antiviral potential of a compound called DTHIB to inhibit HSF1, suppress HCMV replication, and eliminate latently infected monocytes.

Description

This project aims to develop a novel therapeutic strategy targeting HSF1 to combat HCMV infection and latency. Human cytomegalovirus (HCMV) infects the majority of people in the world and can cause serious disease in immunocompromised patients and neonates. The virus establishes life-long latency in bone marrow cells and disseminates to peripheral organs in quiescently infected monocytes. Antiviral therapy delays virus replication, but does not eliminate infected cells. Virus rebound, resistance, and drug toxicity complicate treatment and create a strong demand for improved therapeutics. The project advocates that the suppression of HCMV replication must be in combination with the killing of infected monocytes. The project found that HCMV infection of fibroblasts and monocytes rapidly stimulated the activity of heat shock factor (HSF) 1, a stress-responsive transcription factor, in a distinct fashion from canonical activation induced by heat shock (HS). Using a novel tool compound called DTHIB, which has been validated to selectively inhibit HSF1 activity, inhibition of HSF1 with DTHIB attenuated HCMV lytic replication and stimulated death of latently infected monocytes. These studies provide the beginnings of a proof-of-concept that HSF1 antagonists may have the capacity to provide the double “hit” necessary to suppress HCMV replication and eliminate latently infected myeloid cells in a single drug.

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