Heat shock protein 90 chaperone activity is required for hepatitis A virus replication

Area of Science:

• Virology
• Molecular Biology
• Cellular Biology

Background:

• Heat shock protein 90 (HSP90) is vital for cellular proteostasis and viral protein maturation.
• HSP90 inhibitors exhibit broad-spectrum antiviral activity by disrupting viral replication.
• Hepatitis A virus (HAV), a picornavirus, was previously thought to replicate independently of HSP90.

Purpose of the Study:

• To investigate the role of HSP90 in Hepatitis A virus (HAV) replication.
• To determine if HAV replication is dependent on HSP90, unlike previous assumptions.

Main Methods:

• Treatment of HAV-infected cell lines and *in vivo* mouse models with HSP90 inhibitors (geldanamycin).
• Label-free proteomics to identify potential HSP90 interactions with viral proteins.
• Assessment of HSP90 inhibitor effects on a subgenomic HAV RNA replicon.

Main Results:

• HAV replication was potently inhibited by HSP90 inhibitors in cell culture (50% inhibitory concentration: 8.7-11.8 nM) and *in vivo*.
• Proteomics suggested HSP90 interacts with HAV capsid proteins, aiding their folding and assembly.
• HSP90 inhibitors significantly blocked replication of a subgenomic HAV replicon, indicating a role in replication organelle assembly.

Conclusions:

• HAV replication is highly dependent on HSP90, challenging the notion of its independence among picornaviruses.
• HSP90 is crucial for HAV genome amplification, potentially more so than for other picornaviruses.
• HSP90's role in HAV extends beyond capsid protein maturation to include replication organelle function.