Abstract

Respiratory syncytial virus F glycoprotein was shown to interact with RhoA and RhoA-derived peptides which were shown to inhibit RSV infection in vitro and in a murine model. In addition, RhoA-derived peptides inhibited other viruses (Parainfluenza virus Type 3 and HIV-1) with similar glycoprotein-mediated membrane fusion mechanisms. Further studies showed that RhoA was activated during RSV infection and that inhibiting RhoA activation could alter the syncytium-forming capacity of the virus, and virus morphogenesis, resulting in less filamentous virus. Inhibiting RhoA targeting to membrane through isoprenylation inhibition, could diminish RSV replication and reduce pathogenicity in the murine model. In part, this works through shifting the assembly of RSV from cholesterol-rich lipid microdomains to other regions of the membrane.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI005030-02
Application #
6822428
Study Section
(VPL)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2003
Total Cost
Indirect Cost

  Institution

Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Gower, Tara L; Pastey, Manoj K; Peeples, Mark E et al. (2005) RhoA signaling is required for respiratory syncytial virus-induced syncytium formation and filamentous virion morphology. J Virol 79:5326-36
Rutigliano, John A; Graham, Barney S (2004) Prolonged production of TNF-alpha exacerbates illness during respiratory syncytial virus infection. J Immunol 173:3408-17
Budge, Philip J; Graham, Barney S (2004) Inhibition of respiratory syncytial virus by RhoA-derived peptides: implications for the development of improved antiviral agents targeting heparin-binding viruses. J Antimicrob Chemother 54:299-302
Budge, Philip J; Li, Yeqiang; Beeler, Judy A et al. (2004) RhoA-derived peptide dimers share mechanistic properties with other polyanionic inhibitors of respiratory syncytial virus (RSV), including disruption of viral attachment and dependence on RSV G. J Virol 78:5015-22
McCurdy, Lewis H; Graham, Barney S (2003) Role of plasma membrane lipid microdomains in respiratory syncytial virus filament formation. J Virol 77:1747-56
Budge, Philip J; Lebowitz, Jacob; Graham, Barney S (2003) Antiviral activity of RhoA-derived peptides against respiratory syncytial virus is dependent on formation of peptide dimers. Antimicrob Agents Chemother 47:3470-7
Gower, T L; Peeples, M E; Collins, P L et al. (2001) RhoA is activated during respiratory syncytial virus infection. Virology 283:188-96
Gower, T L; Graham, B S (2001) Antiviral activity of lovastatin against respiratory syncytial virus in vivo and in vitro. Antimicrob Agents Chemother 45:1231-7
Pastey, M K; Gower, T L; Spearman, P W et al. (2000) A RhoA-derived peptide inhibits syncytium formation induced by respiratory syncytial virus and parainfluenza virus type 3. Nat Med 6:35-40