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11:28
Dissecting Host-virus Interaction in Lytic Replication of a Model Herpesvirus
Published on: October 7, 2011
Rapamycin-resistant mTORC1 kinase activity is required for herpesvirus replication
Nathaniel J Moorman1, Thomas Shenk
1Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014, USA.
Journal of Virology
|February 26, 2010
Summary
Torin1, an mTOR kinase inhibitor, blocks human cytomegalovirus replication by disrupting viral DNA synthesis and late protein production, unlike rapamycin. This highlights mTOR kinase inhibitors as potential broad-spectrum antiviral agents.
Area of Science:
- Virology
- Molecular Biology
- Biochemistry
Background:
- Human cytomegalovirus (HCMV) infection activates the mTORC1 signaling pathway.
- The mTORC1 inhibitor rapamycin shows limited efficacy in inhibiting HCMV replication.
- HCMV replication involves both rapamycin-sensitive and rapamycin-resistant mTOR activity.
Purpose of the Study:
- To investigate the role of mTOR kinase activity in HCMV replication using the inhibitor Torin1.
- To elucidate the mechanism by which Torin1 inhibits HCMV replication.
- To assess the potential of mTOR kinase inhibitors as broad-spectrum antiviral agents.
Main Methods:
- Treatment of infected cells with Torin1 and rapamycin.
- Analysis of mTORC1 target phosphorylation and eIF4F complex assembly.
- Assessment of viral protein and DNA accumulation.
- Utilizing murine fibroblasts with specific mutations to study MCMV replication.
- Testing Torin1 against various herpesvirus families.
Main Results:
- Torin1 markedly blocks HCMV progeny production by inhibiting both rapamycin-sensitive and resistant mTOR targets.
- Torin1 disrupts eIF4F complex assembly and increases 4EBP1 association with the cap-binding complex.
- Torin1 significantly decreases viral DNA and late protein (pUL99) accumulation, but not viral entry or early protein synthesis.
- Torin1-mediated inhibition of MCMV replication is independent of mTORC2 and Akt kinases but dependent on 4EBP1.
- Torin1 inhibits replication of alpha-, beta-, and gammaherpesviruses.
Conclusions:
- HCMV replication requires both rapamycin-sensitive and rapamycin-resistant mTOR activity.
- Torin1 effectively inhibits HCMV replication by targeting mTOR kinase activity, impacting viral DNA and late protein synthesis.
- Inactivation of 4EBP1 by mTORC1 is critical for cytomegalovirus replication.
- mTOR kinase inhibitors demonstrate broad-spectrum antiviral potential against herpesviruses.
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