Dengue and yellow fever virus are significant human pathogens that cause hemorrhagic fever and fatalities. Currently, there are no approved antivirals for these viruses. The development of antivirals for RNA viruses has proven to be particularly difficult due to the rapid emergence of drug resistant viruses. This is primarily due to the error prone nature of the polymerase, which results in rapid evolution of the virus under selective pressure. Targeting a host factor for which the virus does not have any genetic control over should decrease or prevent development of resistant mutants either because the virus cannot function without the host factor or because more mutations are required to confer resistance. Towards this goal we have developed a robust method to identify host factors that are bound to the viral RNA during viral amplification i cell culture. We will use this method to identify host factors that are bound to the dengue virus and yellow fever virus RNA. We will identify which host factors will be good targets to develop antiviral targets. In addition, we will also determine the step in the viral life cycle the host fators participate in and the protein-protein and protein-viral RNA interactions for that host factor during viral infection. These studies will address the mechanism of the host factor in viral amplification and enable development of a high-throughput assay fro inhibitors of the host factor.

Public Health Relevance

RNA viruses rapidly evolve resistant viruses to antiviral that target the viral proteins. An antivial that targets a host protein would significantly reduce or prevent drug resistance. Therefore, we will identify host factors that interact with dengue and yellow fever viral RNAs and determine their role in the viral life cycle in order to identify an effective antiviral target.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI102187-02
Application #
8522155
Study Section
Special Emphasis Panel (ZAI1-RRS-M (M2))
Program Officer
Cassetti, Cristina
Project Start
2012-08-03
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$194,348
Indirect Cost
$38,239
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Greco, Todd M; Guise, Amanda J; Cristea, Ileana M (2016) Determining the Composition and Stability of Protein Complexes Using an Integrated Label-Free and Stable Isotope Labeling Strategy. Methods Mol Biol 1410:39-63
Ashford, Paul; Hernandez, Anna; Greco, Todd Michael et al. (2016) HVint: A Strategy for Identifying Novel Protein-Protein Interactions in Herpes Simplex Virus Type 1. Mol Cell Proteomics 15:2939-53
Song, Ren; Koyuncu, Orkide O; Greco, Todd M et al. (2016) Two Modes of the Axonal Interferon Response Limit Alphaherpesvirus Neuroinvasion. MBio 7:e02145-15
Castellana, Michele; Hsin-Jung Li, Sophia; Wingreen, Ned S (2016) Spatial organization of bacterial transcription and translation. Proc Natl Acad Sci U S A 113:9286-91
Lum, Krystal K; Cristea, Ileana M (2016) Proteomic approaches to uncovering virus-host protein interactions during the progression of viral infection. Expert Rev Proteomics 13:325-40
Mathias, Rommel A; Greco, Todd M; Cristea, Ileana M (2016) Identification of Sirtuin4 (SIRT4) Protein Interactions: Uncovering Candidate Acyl-Modified Mitochondrial Substrates and Enzymatic Regulators. Methods Mol Biol 1436:213-39
Jean Beltran, Pierre M; Mathias, Rommel A; Cristea, Ileana M (2016) A Portrait of the Human Organelle Proteome In Space and Time during Cytomegalovirus Infection. Cell Syst 3:361-373.e6
Budayeva, Hanna G; Rowland, Elizabeth A; Cristea, Ileana M (2016) Intricate Roles of Mammalian Sirtuins in Defense against Viral Pathogens. J Virol 90:5-8
Luo, Yang; Jacobs, Erica Y; Greco, Todd M et al. (2016) HIV-host interactome revealed directly from infected cells. Nat Microbiol 1:16068
Crow, Marni S; Lum, Krystal K; Sheng, Xinlei et al. (2016) Diverse mechanisms evolved by DNA viruses to inhibit early host defenses. Crit Rev Biochem Mol Biol :1-30

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