Fitness landscape of the human immunodeficiency virus envelope protein that is targeted by antibodies
Name
E564.full.pdf
Size
1.31 MB
Format
Adobe PDF
Checksum (MD5)
b17ccb1b29cdc275739feb1e8a01a843
Author(s)
Louie, Raymond H. Y.
Kaczorowski, Kevin John
Barton, John P
Chakraborty, Arup K
McKay, Matthew
Date Issued
December 2017
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Louie, Raymond H. Y. et al. “Fitness Landscape of the Human Immunodeficiency Virus Envelope Protein That Is Targeted by Antibodies.” Proceedings of the National Academy of Sciences 115, 4 (January 2018): E564–E573 © 2018 the Author(s)
Version
Final published version
Abstract
HIV is a highly mutable virus, and over 30 years after its discovery, a vaccine or cure is still not available. The isolation of broadly neutralizing antibodies (bnAbs) from HIV-infected patients has led to renewed hope for a prophylactic vaccine capable of combating the scourge of HIV. A major challenge is the design of immunogens and vaccination protocols that can elicit bnAbs that target regions of the virus’s spike proteins where the likelihood of mutational escape is low due to the high fitness cost of mutations. Related challenges include the choice of combinations of bnAbs for therapy. An accurate representation of viral fitness as a function of its protein sequences (a fitness landscape), with explicit accounting of the effects of coupling between mutations, could help address these challenges. We describe a computational approach that has allowed us to infer a fitness landscape for gp160, the HIV polyprotein that comprises the viral spike that is targeted by antibodies. We validate the inferred landscape through comparisons with experimental fitness measurements, and various other metrics. We show that an effective antibody that prevents immune escape must selectively bind to high escape cost residues that are surrounded by those where mutations incur a low fitness cost, motivating future applications of our landscape for immunogen design. Keywords: HIV; fitness landscape; envelope protein; statistical inference; broadly neutralizing antibodies
MIT Department
Institute for Medical Engineering and Science
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Physics
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1073/PNAS.1717765115
