RNA viruses are a significant cause of morbidity and mortality in humans. Some representatives of this large group of pathogens are hepatitis A, B and C viruses, HIV, influenza virus, most of the cold viruses, rabies virus, Ebola virus, West Nile virus, and dengue virus. We face major difficulties in controlling these viral diseases because of the viruses'escape from immune responses, escape from antiviral drugs, and the emergence of new viruses from animal reservoirs. All these difficulties are caused by the same process: RNA viruses rapidly adapt to new challenges in their environment. This rapid adaptation is possible because RNA virus populations are extremely heterogeneous. Among the variants in a viral population there are usually mutants capable of replicating in the presence of antibodies, antiviral drugs, or in new host cells. New therapies must be designed such that the development of resistance can be prevented or at least substantially delayed. However, we currently have no systematic strategy to develop such therapies, and the predominant approach is trial-and-error. This proposal will continue to build a framework of RNA virus evolution that will be used to develop improved antiviral strategies in a rational way. We use a unique approach of experimental virus evolution (which includes detailed phenotypic and genotypic analyses) combined with computer simulation to address fundamental questions of viral adaptation. We propose to study genetic and environmental determinants that lead to fitness changes and to differences in the potential of a virus population to adapt. Our model system is vesicular stomatitis virus, a well characterized and widely studied virus. We will evaluate three aspects of RNA virus evolution: (i) The genetic basis of differences in adaptability;(ii) the effect of two environmental determinants, population size and population density, on the speed of evolution and the maintenance of variation;and (iii) the consequences of interactions between genetic components and environmental components for virus evolution.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065960-05
Application #
7575630
Study Section
Virology - B Study Section (VIRB)
Program Officer
Cassetti, Cristina
Project Start
2005-06-15
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2011-02-28
Support Year
5
Fiscal Year
2009
Total Cost
$368,679
Indirect Cost
Name
University of Toledo
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Smith-Tsurkan, Sarah D; Herr, Roger A; Khuder, Sadik et al. (2013) The role of environmental factors on the evolution of phenotypic diversity in vesicular stomatitis virus populations. J Gen Virol 94:860-8
Novella, Isabel S; Presloid, John B; Smith, Sarah D et al. (2011) Specific and nonspecific host adaptation during arboviral experimental evolution. J Mol Microbiol Biotechnol 21:71-81
O'Dea, Eamon B; Keller, Thomas E; Wilke, Claus O (2010) Does mutational robustness inhibit extinction by lethal mutagenesis in viral populations? PLoS Comput Biol 6:e1000811
Novella, Isabel S; Presloid, John B; Zhou, Tong et al. (2010) Genomic evolution of vesicular stomatitis virus strains with differences in adaptability. J Virol 84:4960-8
Smith-Tsurkan, Sarah D; Wilke, Claus O; Novella, Isabel S (2010) Incongruent fitness landscapes, not tradeoffs, dominate the adaptation of vesicular stomatitis virus to novel host types. J Gen Virol 91:1484-93
Zhou, Tong; Gu, Wanjun; Wilke, Claus O (2010) Detecting positive and purifying selection at synonymous sites in yeast and worm. Mol Biol Evol 27:1912-22
Steinmeyer, Shelby H; Wilke, Claus O (2009) Lethal mutagenesis in a structured environment. J Theor Biol 261:67-73
Brennan, Timothy P; Woods, John O; Sedaghat, Ahmad R et al. (2009) Analysis of human immunodeficiency virus type 1 viremia and provirus in resting CD4+ T cells reveals a novel source of residual viremia in patients on antiretroviral therapy. J Virol 83:8470-81
Zhou, Tong; Weems, Mason; Wilke, Claus O (2009) Translationally optimal codons associate with structurally sensitive sites in proteins. Mol Biol Evol 26:1571-80
Sedaghat, Ahmad R; Siliciano, Robert F; Wilke, Claus O (2009) Constraints on the dominant mechanism for HIV viral dynamics in patients on raltegravir. Antivir Ther 14:263-71

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