This proposal outlines a two-year transitional grant for Jesse D. Bloom, Ph.D. The grant would be activated once Dr. Bloom begins an assistant professor position at a research institution, and would be used to fund the initial years of his work. Dr. Bloom is currently a postdoctoral scholar in the laboratory of Dr. David Baltimore at the California Institute of Technology. Dr. Bloom's research examines molecular constraints on viral evolution. This specific proposal deals with the evolution of oseltamivir (Tamiflu) resistance in H1N1 influenza viruses via the His274->Tyr (H274Y) mutation to the neuraminidase protein. This resistance mutation had long been thought unlikely to spread since it attenuated seasonal H1N1 viruses, but it recently spread worldwide. Dr. Bloom's preliminary research has shown that this global spread of H274Y was enabled by secondary "permissive" mutations that rescued a defect that H274Y caused in the surface expression of neuraminidase protein. The proposed research will examine in detail the biophysical defect caused by H274Y, and the mechanism by which it affects viral growth in tissue culture and animal models. In order to aid in the identification of other possible permissive mutations that might enable the evolutionary spread of H274Y, the research will develop and test computational prediction methods. Finally, these computational and experimental tools will be used towards forecasting the potential for H274Y to confer widespread oseltamivir resistance on the swine-origin 2009 pandemic H1N1 influenza strain. The proposed work will therefore represent a substantial step towards the goal of predicting virus evolution. Progress towards this goal will be of public health value in regards to medically important viruses such as influenza. Public Health Relevance: Viral diseases such as influenza are so problematic because they rapidly evolve to escape immunity and antiviral drugs. This proposal examines a specific example of viral escape, the evolution of oseltamivir (Tamiflu) resistance in H1N1 influenza. The goal is to understand this escape at a molecular level, and use the resulting insight to anticipate potential future routes of oseltamivir resistance.

Public Health Relevance

Viral diseases such as influenza are so problematic because they rapidly evolve to escape immunity and antiviral drugs. This proposal examines a specific example of viral escape, the evolution of oseltamivir (Tamiflu) resistance in H1N1 influenza. The goal is to understand this escape at a molecular level, and use the resulting insight to anticipate potential future routes of oseltamivir resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Career Transition Award (K22)
Project #
5K22AI093789-02
Application #
8324193
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Krafft, Amy
Project Start
2011-09-01
Project End
2014-01-31
Budget Start
2012-09-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$106,162
Indirect Cost
$7,864
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Butler, Jeff; Hooper, Kathryn A; Petrie, Stephen et al. (2014) Estimating the fitness advantage conferred by permissive neuraminidase mutations in recent oseltamivir-resistant A(H1N1)pdm09 influenza viruses. PLoS Pathog 10:e1004065
Hooper, Kathryn A; Bloom, Jesse D (2013) A mutant influenza virus that uses an N1 neuraminidase as the receptor-binding protein. J Virol 87:12531-40
Balazs, Alejandro B; Bloom, Jesse D; Hong, Christin M et al. (2013) Broad protection against influenza infection by vectored immunoprophylaxis in mice. Nat Biotechnol 31:647-52