Cargando…

Fitness landscape of the human immunodeficiency virus envelope protein that is targeted by antibodies

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 chal...

Descripción completa

Detalles Bibliográficos
Autores principales: Louie, Raymond H. Y., Kaczorowski, Kevin J., Barton, John P., Chakraborty, Arup K., McKay, Matthew R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789945/
https://www.ncbi.nlm.nih.gov/pubmed/29311326
http://dx.doi.org/10.1073/pnas.1717765115
_version_ 1783296377961316352
author Louie, Raymond H. Y.
Kaczorowski, Kevin J.
Barton, John P.
Chakraborty, Arup K.
McKay, Matthew R.
author_facet Louie, Raymond H. Y.
Kaczorowski, Kevin J.
Barton, John P.
Chakraborty, Arup K.
McKay, Matthew R.
author_sort Louie, Raymond H. Y.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5789945
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-57899452018-02-03 Fitness landscape of the human immunodeficiency virus envelope protein that is targeted by antibodies Louie, Raymond H. Y. Kaczorowski, Kevin J. Barton, John P. Chakraborty, Arup K. McKay, Matthew R. Proc Natl Acad Sci U S A PNAS Plus 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. National Academy of Sciences 2018-01-23 2018-01-08 /pmc/articles/PMC5789945/ /pubmed/29311326 http://dx.doi.org/10.1073/pnas.1717765115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Louie, Raymond H. Y.
Kaczorowski, Kevin J.
Barton, John P.
Chakraborty, Arup K.
McKay, Matthew R.
Fitness landscape of the human immunodeficiency virus envelope protein that is targeted by antibodies
title Fitness landscape of the human immunodeficiency virus envelope protein that is targeted by antibodies
title_full Fitness landscape of the human immunodeficiency virus envelope protein that is targeted by antibodies
title_fullStr Fitness landscape of the human immunodeficiency virus envelope protein that is targeted by antibodies
title_full_unstemmed Fitness landscape of the human immunodeficiency virus envelope protein that is targeted by antibodies
title_short Fitness landscape of the human immunodeficiency virus envelope protein that is targeted by antibodies
title_sort fitness landscape of the human immunodeficiency virus envelope protein that is targeted by antibodies
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789945/
https://www.ncbi.nlm.nih.gov/pubmed/29311326
http://dx.doi.org/10.1073/pnas.1717765115
work_keys_str_mv AT louieraymondhy fitnesslandscapeofthehumanimmunodeficiencyvirusenvelopeproteinthatistargetedbyantibodies
AT kaczorowskikevinj fitnesslandscapeofthehumanimmunodeficiencyvirusenvelopeproteinthatistargetedbyantibodies
AT bartonjohnp fitnesslandscapeofthehumanimmunodeficiencyvirusenvelopeproteinthatistargetedbyantibodies
AT chakrabortyarupk fitnesslandscapeofthehumanimmunodeficiencyvirusenvelopeproteinthatistargetedbyantibodies
AT mckaymatthewr fitnesslandscapeofthehumanimmunodeficiencyvirusenvelopeproteinthatistargetedbyantibodies