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 in 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 factors 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 antiviral 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 Phase II (R33)
Project #
4R33AI102187-03
Application #
8889884
Study Section
Special Emphasis Panel (NSS)
Program Officer
Cassetti, Cristina
Project Start
2014-08-20
Project End
2016-07-31
Budget Start
2014-08-20
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
$392,751
Indirect Cost
$82,215
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Shi, Bi; Geng, Jianlin; Wang, Yin-Hu et al. (2018) Foxp1 Negatively Regulates T Follicular Helper Cell Differentiation and Germinal Center Responses by Controlling Cell Migration and CTLA-4. J Immunol 200:586-594
Jean Beltran, Pierre M; Federspiel, Joel D; Sheng, Xinlei et al. (2017) Proteomics and integrative omic approaches for understanding host-pathogen interactions and infectious diseases. Mol Syst Biol 13:922
Rowland, Elizabeth A; Greco, Todd M; Snowden, Caroline K et al. (2017) Sirtuin Lipoamidase Activity Is Conserved in Bacteria as a Regulator of Metabolic Enzyme Complexes. MBio 8:
Carvajal, Felipe; Vallejos, Maricarmen; Walters, Beth et al. (2016) Structural domains within the HIV-1 mRNA and the ribosomal protein S25 influence cap-independent translation initiation. FEBS J 283:2508-27
Viktorovskaya, Olga V; Greco, Todd M; Cristea, Ileana M et al. (2016) Identification of RNA Binding Proteins Associated with Dengue Virus RNA in Infected Cells Reveals Temporally Distinct Host Factor Requirements. PLoS Negl Trop Dis 10:e0004921
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 51:452-481
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
Luo, Yang; Jacobs, Erica Y; Greco, Todd M et al. (2016) HIV-host interactome revealed directly from infected cells. Nat Microbiol 1:16068
Guise, Amanda J; Cristea, Ileana M (2016) Approaches for Studying the Subcellular Localization, Interactions, and Regulation of Histone Deacetylase 5 (HDAC5). Methods Mol Biol 1436:47-84
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

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