Cargando…
CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity
During the entry process, the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer undergoes a sequence of conformational changes triggered by both CD4 and coreceptor engagement. Resolving the conformation of these transient entry intermediates has proven challenging. Here,...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351000/ https://www.ncbi.nlm.nih.gov/pubmed/30650070 http://dx.doi.org/10.1371/journal.pbio.3000114 |
_version_ | 1783390527355355136 |
---|---|
author | Ivan, Branislav Sun, Zhaozhi Subbaraman, Harini Friedrich, Nikolas Trkola, Alexandra |
author_facet | Ivan, Branislav Sun, Zhaozhi Subbaraman, Harini Friedrich, Nikolas Trkola, Alexandra |
author_sort | Ivan, Branislav |
collection | PubMed |
description | During the entry process, the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer undergoes a sequence of conformational changes triggered by both CD4 and coreceptor engagement. Resolving the conformation of these transient entry intermediates has proven challenging. Here, we fine-mapped the antigenicity of entry intermediates induced by increasing CD4 engagement of cell surface–expressed Env. Escalating CD4 triggering led to the sequential adoption of different pre-fusion conformational states of the Env trimer, up to the pre-hairpin conformation, that we assessed for antibody epitope presentation. Maximal accessibility of the coreceptor binding site was detected below Env saturation by CD4. Exposure of the fusion peptide and heptad repeat 1 (HR1) required higher CD4 occupancy. Analyzing the diverse antigenic states of the Env trimer, we obtained key insights into the transitions in epitope accessibility of broadly neutralizing antibodies (bnAbs). Several bnAbs preferentially bound CD4-triggered Env, indicating a potential capacity to neutralize both pre- and post-CD4 engagement, which needs to be explored. Assessing binding and neutralization activity of bnAbs, we confirm antibody dissociation rates as a driver of incomplete neutralization. Collectively, our findings highlight a need to resolve Env conformations that are neutralization-relevant to provide guidance for immunogen development. |
format | Online Article Text |
id | pubmed-6351000 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-63510002019-02-15 CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity Ivan, Branislav Sun, Zhaozhi Subbaraman, Harini Friedrich, Nikolas Trkola, Alexandra PLoS Biol Research Article During the entry process, the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer undergoes a sequence of conformational changes triggered by both CD4 and coreceptor engagement. Resolving the conformation of these transient entry intermediates has proven challenging. Here, we fine-mapped the antigenicity of entry intermediates induced by increasing CD4 engagement of cell surface–expressed Env. Escalating CD4 triggering led to the sequential adoption of different pre-fusion conformational states of the Env trimer, up to the pre-hairpin conformation, that we assessed for antibody epitope presentation. Maximal accessibility of the coreceptor binding site was detected below Env saturation by CD4. Exposure of the fusion peptide and heptad repeat 1 (HR1) required higher CD4 occupancy. Analyzing the diverse antigenic states of the Env trimer, we obtained key insights into the transitions in epitope accessibility of broadly neutralizing antibodies (bnAbs). Several bnAbs preferentially bound CD4-triggered Env, indicating a potential capacity to neutralize both pre- and post-CD4 engagement, which needs to be explored. Assessing binding and neutralization activity of bnAbs, we confirm antibody dissociation rates as a driver of incomplete neutralization. Collectively, our findings highlight a need to resolve Env conformations that are neutralization-relevant to provide guidance for immunogen development. Public Library of Science 2019-01-16 /pmc/articles/PMC6351000/ /pubmed/30650070 http://dx.doi.org/10.1371/journal.pbio.3000114 Text en © 2019 Ivan et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Ivan, Branislav Sun, Zhaozhi Subbaraman, Harini Friedrich, Nikolas Trkola, Alexandra CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity |
title | CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity |
title_full | CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity |
title_fullStr | CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity |
title_full_unstemmed | CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity |
title_short | CD4 occupancy triggers sequential pre-fusion conformational states of the HIV-1 envelope trimer with relevance for broadly neutralizing antibody activity |
title_sort | cd4 occupancy triggers sequential pre-fusion conformational states of the hiv-1 envelope trimer with relevance for broadly neutralizing antibody activity |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351000/ https://www.ncbi.nlm.nih.gov/pubmed/30650070 http://dx.doi.org/10.1371/journal.pbio.3000114 |
work_keys_str_mv | AT ivanbranislav cd4occupancytriggerssequentialprefusionconformationalstatesofthehiv1envelopetrimerwithrelevanceforbroadlyneutralizingantibodyactivity AT sunzhaozhi cd4occupancytriggerssequentialprefusionconformationalstatesofthehiv1envelopetrimerwithrelevanceforbroadlyneutralizingantibodyactivity AT subbaramanharini cd4occupancytriggerssequentialprefusionconformationalstatesofthehiv1envelopetrimerwithrelevanceforbroadlyneutralizingantibodyactivity AT friedrichnikolas cd4occupancytriggerssequentialprefusionconformationalstatesofthehiv1envelopetrimerwithrelevanceforbroadlyneutralizingantibodyactivity AT trkolaalexandra cd4occupancytriggerssequentialprefusionconformationalstatesofthehiv1envelopetrimerwithrelevanceforbroadlyneutralizingantibodyactivity |