CaltechAUTHORS
  A Caltech Library Service

A Computational-Experimental Approach Identifies Mutations That Enhance Surface Expression of an Oseltamivir-Resistant Influenza Neuraminidase

Bloom, Jesse D. and Nayak, Jagannath S. and Baltimore, David (2011) A Computational-Experimental Approach Identifies Mutations That Enhance Surface Expression of an Oseltamivir-Resistant Influenza Neuraminidase. PLoS ONE, 6 (7). Art. No. e22201. ISSN 1932-6203. PMCID PMC3140507. https://resolver.caltech.edu/CaltechAUTHORS:20110812-085604415

[img]
Preview
PDF - Published Version
Creative Commons Attribution.

612Kb

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20110812-085604415

Abstract

The His274 → Tyr (H274Y) oseltamivir (Tamiflu) resistance mutation causes a substantial decrease in the total levels of surface-expressed neuraminidase protein and activity in early isolates of human seasonal H1N1 influenza, and in the swine-origin pandemic H1N1. In seasonal H1N1, H274Y only became widespread after the occurrence of secondary mutations that counteracted this decrease. H274Y is currently rare in pandemic H1N1, and it remains unclear whether secondary mutations exist that might similarly counteract the decreased neuraminidase surface expression associated with this resistance mutation in pandemic H1N1. Here we investigate the possibility of predicting such secondary mutations. We first test the ability of several computational approaches to retrospectively identify the secondary mutations that enhanced levels of surface-expressed neuraminidase protein and activity in seasonal H1N1 shortly before the emergence of oseltamivir resistance. We then use the most successful computational approach to predict a set of candidate secondary mutations to the pandemic H1N1 neuraminidase. We experimentally screen these mutations, and find that several of them do indeed partially counteract the decrease in neuraminidase surface expression caused by H274Y. Two of the secondary mutations together restore surface-expressed neuraminidase activity to wildtype levels, and also eliminate the very slight decrease in viral growth in tissue-culture caused by H274Y. Our work therefore demonstrates a combined computational-experimental approach for identifying mutations that enhance neuraminidase surface expression, and describes several specific mutations with the potential to be of relevance to the spread of oseltamivir resistance in pandemic H1N1.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1371/journal.pone.0022201DOIArticle
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0022201PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140507/PubMed CentralArticle
ORCID:
AuthorORCID
Bloom, Jesse D.0000-0003-1267-3408
Baltimore, David0000-0001-8723-8190
Additional Information:© 2011 Bloom et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received May 5, 2011; Accepted June 16, 2011; Published July 20, 2011. Editor: Ron A. M. Fouchier, Erasmus Medical Center, Netherlands. Funding: JDB was funded by a Beckman Institute postdoctoral fellowship at the California Institute of Technology. JSN was funded by an Amgen undergraduate summer research fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author Contributions: Conceived and designed the experiments: JDB DB. Performed the experiments: JDB JSN. Analyzed the data: JDB. Wrote the paper: JDB DB.
Funders:
Funding AgencyGrant Number
Caltech Beckman Institute UNSPECIFIED
Amgen UNSPECIFIED
Issue or Number:7
PubMed Central ID:PMC3140507
Record Number:CaltechAUTHORS:20110812-085604415
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20110812-085604415
Official Citation:Bloom JD, Nayak JS, Baltimore D (2011) A Computational-Experimental Approach Identifies Mutations That Enhance Surface Expression of an Oseltamivir-Resistant Influenza Neuraminidase. PLoS ONE 6(7): e22201. doi:10.1371/journal.pone.0022201
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:24817
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:17 Oct 2011 16:47
Last Modified:03 Oct 2019 03:00

Repository Staff Only: item control page