An RNA virus population does not consist of a single genotype;rather, it is an ensemble of related sequences, termed quasispecies. High mutation rates of RNA viral replication create a 'cloud'of potentially beneficial mutations at the population level, which afford the viral quasispecies a greater probability to evolve and adapt to new environments and challenges during infection. Using poliovirus as our model we developed strategies to increase or reduce the mutation rate of the viral polymerase thus changing the levels of genomic diversity in the viral population. In infected animals, reducing or increasing viral diversity leads to loss of neurotropism and an attenuated pathogenic phenotype. These findings suggest that quasispecies diversity is finely tuned to ensure evolutionary survival of the virus and is a biological determinant for the outcome of poliovirus infection. The long-term goal of this proposal is to examine the significance of genome diversity for virus pathogenesis. Our research will have important consequences for the understanding of viral pathogenesis and for the development of live attenuated viral vaccines. Specifically we propose to: (1) characterize the relationship between polymerase fidelity and the generation of viral quasispecies;(2) determine the relationship between viral quasispecies diversity, fitness and adaptability;(3) characterize the relationship between quasispecies diversity and pathogenesis in vivo, in infected animals, (4) explore the possibility of developing live- attenuated virus vaccines by altering quasispecies diversity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036178-16
Application #
8039883
Study Section
Virology - B Study Section (VIRB)
Program Officer
Park, Eun-Chung
Project Start
1994-08-01
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2014-03-31
Support Year
16
Fiscal Year
2011
Total Cost
$427,920
Indirect Cost
Name
University of California San Francisco
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Dolan, Patrick T; Whitfield, Zachary J; Andino, Raul (2018) Mapping the Evolutionary Potential of RNA Viruses. Cell Host Microbe 23:435-446
Lidsky, Peter V; Lukyanov, Konstantin A; Misra, Tvisha et al. (2018) A genetically encoded fluorescent probe for imaging of oxygenation gradients in living Drosophila. Development 145:
Xiao, Yinghong; Dolan, Patrick Timothy; Goldstein, Elizabeth Faul et al. (2017) Poliovirus intrahost evolution is required to overcome tissue-specific innate immune responses. Nat Commun 8:375
Lidsky, Peter V; Andino, Raul; Rouzine, Igor M (2017) Variability in viral pathogenesis: modeling the dynamic of acute and persistent infections. Curr Opin Virol 23:120-124
Menéndez-Arias, Luis; Andino, Raul (2017) Viral polymerases. Virus Res 234:1-3
Whitfield, Zachary J; Dolan, Patrick T; Kunitomi, Mark et al. (2017) The Diversity, Structure, and Function of Heritable Adaptive Immunity Sequences in the Aedes aegypti Genome. Curr Biol 27:3511-3519.e7
Stern, Adi; Yeh, Ming Te; Zinger, Tal et al. (2017) The Evolutionary Pathway to Virulence of an RNA Virus. Cell 169:35-46.e19
Xiao, Yinghong; Rouzine, Igor M; Bianco, Simone et al. (2017) RNA Recombination Enhances Adaptability and Is Required for Virus Spread and Virulence. Cell Host Microbe 22:420
Tassetto, Michel; Kunitomi, Mark; Andino, Raul (2017) Circulating Immune Cells Mediate a Systemic RNAi-Based Adaptive Antiviral Response in Drosophila. Cell 169:314-325.e13
Xiao, Yinghong; Rouzine, Igor M; Bianco, Simone et al. (2016) RNA Recombination Enhances Adaptability and Is Required for Virus Spread and Virulence. Cell Host Microbe 19:493-503

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