Fitness landscape of the human immunodeficiency virus envelope protein that is targeted by antibodies
Author(s)
Louie, Raymond H. Y.; Kaczorowski, Kevin John; Barton, John P; Chakraborty, Arup K; McKay, Matthew
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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
Date issued
2017-12Department
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 PhysicsJournal
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
ISSN
0027-8424
1091-6490