Infection by viruses in the Togaviridae family causes significant worldwide morbidity and mortality. There is currently no specific treatment for patients infected with any virus from this family. Viruses in the Alphavirus genus cause diseases ranging from fever, rash and arthritis to fatal encephalitis. Several members of this genus have been identified as possible agents of bioterrorism. Our preliminary studies indicate that the rat zinc-finger antiviral protein (ZAP), which was originally discovered as a host protein that inhibits replication of retroviruses, potently inhibits replication of multiple members of the Alphavirus genus. Sindbis virus (SIN), Ross River virus, Semliki Forest virus and Venezuelan equine encephalitis virus replication were all inhibited to varying extents. The long-term objectives of this project are to elucidate, using virological, molecular and cell biological approaches, the mechanism(s) by which ZAP inhibits replication of alphaviruses. Investigations using SIN, which has been studied extensively and is dramatically inhibited by ZAP, show that replication is blocked after entry and at or before translation of the incoming plus strand genomic viral RNA. Experiments outlined in this proposal will determine the relationship between ZAP levels and SIN replication, and will investigate the mechanism by which ZAP blocks SIN RNA translation. We will characterize the interaction between ZAP and the SIN RNA, as well as the interaction, if any, between ZAP and other host or viral factors. Understanding the mechanism of ZAP's inhibition of alphavirus replication may lead to the development of new therapeutic or preventative agents for illness due to alphavirus infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI057905-01A2
Application #
6917701
Study Section
Virology - B Study Section (VIRB)
Program Officer
Repik, Patricia M
Project Start
2005-03-01
Project End
2010-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
1
Fiscal Year
2005
Total Cost
$379,875
Indirect Cost
Name
Rockefeller University
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
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Charron, Guillaume; Li, Melody M H; MacDonald, Margaret R et al. (2013) Prenylome profiling reveals S-farnesylation is crucial for membrane targeting and antiviral activity of ZAP long-isoform. Proc Natl Acad Sci U S A 110:11085-90
Karki, Sophiya; Li, Melody M H; Schoggins, John W et al. (2012) Multiple interferon stimulated genes synergize with the zinc finger antiviral protein to mediate anti-alphavirus activity. PLoS One 7:e37398
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MacDonald, Margaret R; Machlin, Erica S; Albin, Owen R et al. (2007) The zinc finger antiviral protein acts synergistically with an interferon-induced factor for maximal activity against alphaviruses. J Virol 81:13509-18