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Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens

A major challenge in HIV vaccine development is the identification of immunogens able to elicit broadly neutralizing antibodies (bNAbs). While remarkable progress has been made in the isolation and characterization of bNAbs, the epitopes they recognize appear to be poorly immunogenic. Thus, none of...

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Autores principales: Mesa, Kathryn A., Yu, Bin, Wrin, Terri, Petropoulos, Christos J., Pogson, Grant H., Alexander, David L., Perez, Gerardo, O’Rourke, Sara M., Sinangil, Faruk, Robinson, Joseph, Conant, Marcus A., Berman, Phillip W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457492/
https://www.ncbi.nlm.nih.gov/pubmed/30969970
http://dx.doi.org/10.1371/journal.pone.0213409
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author Mesa, Kathryn A.
Yu, Bin
Wrin, Terri
Petropoulos, Christos J.
Pogson, Grant H.
Alexander, David L.
Perez, Gerardo
O’Rourke, Sara M.
Sinangil, Faruk
Robinson, Joseph
Conant, Marcus A.
Berman, Phillip W.
author_facet Mesa, Kathryn A.
Yu, Bin
Wrin, Terri
Petropoulos, Christos J.
Pogson, Grant H.
Alexander, David L.
Perez, Gerardo
O’Rourke, Sara M.
Sinangil, Faruk
Robinson, Joseph
Conant, Marcus A.
Berman, Phillip W.
author_sort Mesa, Kathryn A.
collection PubMed
description A major challenge in HIV vaccine development is the identification of immunogens able to elicit broadly neutralizing antibodies (bNAbs). While remarkable progress has been made in the isolation and characterization of bNAbs, the epitopes they recognize appear to be poorly immunogenic. Thus, none of the candidate vaccines developed to date has induced satisfactory levels of neutralizing antibodies to the HIV envelope protein (Env). One approach to the problem of poor immunogenicity is to build vaccines based on envelope (env) genes retrieved from rare individuals termed elite neutralizers (ENs) who at one time possessed specific sequences that stimulated the formation of bNAbs. Env proteins selected from these individuals could possess uncommon, yet to be defined, structural features that enhance the immunogenicity of epitopes recognized by bNAbs. Here we describe the recovery of envs from an EN that developed unusually broad and potent bNAbs. As longitudinal specimens were not available, we combined plasma and provirus sequences acquired from a single time-point to infer a phylogenetic tree. Combining ancestral reconstruction data with virus neutralization data allowed us to sift through the myriad of virus quasi-species that evolved in this individual to identify envelope sequences from the nodes that appeared to define the transition from neutralization sensitive envs to the neutralization resistant envs that occur in EN plasma. Synthetic genes from these nodes were functional in infectivity assays and sensitive to neutralization by bNAbs, and may provide a novel source of immunogens for HIV vaccine development.
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spelling pubmed-64574922019-05-03 Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens Mesa, Kathryn A. Yu, Bin Wrin, Terri Petropoulos, Christos J. Pogson, Grant H. Alexander, David L. Perez, Gerardo O’Rourke, Sara M. Sinangil, Faruk Robinson, Joseph Conant, Marcus A. Berman, Phillip W. PLoS One Research Article A major challenge in HIV vaccine development is the identification of immunogens able to elicit broadly neutralizing antibodies (bNAbs). While remarkable progress has been made in the isolation and characterization of bNAbs, the epitopes they recognize appear to be poorly immunogenic. Thus, none of the candidate vaccines developed to date has induced satisfactory levels of neutralizing antibodies to the HIV envelope protein (Env). One approach to the problem of poor immunogenicity is to build vaccines based on envelope (env) genes retrieved from rare individuals termed elite neutralizers (ENs) who at one time possessed specific sequences that stimulated the formation of bNAbs. Env proteins selected from these individuals could possess uncommon, yet to be defined, structural features that enhance the immunogenicity of epitopes recognized by bNAbs. Here we describe the recovery of envs from an EN that developed unusually broad and potent bNAbs. As longitudinal specimens were not available, we combined plasma and provirus sequences acquired from a single time-point to infer a phylogenetic tree. Combining ancestral reconstruction data with virus neutralization data allowed us to sift through the myriad of virus quasi-species that evolved in this individual to identify envelope sequences from the nodes that appeared to define the transition from neutralization sensitive envs to the neutralization resistant envs that occur in EN plasma. Synthetic genes from these nodes were functional in infectivity assays and sensitive to neutralization by bNAbs, and may provide a novel source of immunogens for HIV vaccine development. Public Library of Science 2019-04-10 /pmc/articles/PMC6457492/ /pubmed/30969970 http://dx.doi.org/10.1371/journal.pone.0213409 Text en © 2019 Mesa 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
Mesa, Kathryn A.
Yu, Bin
Wrin, Terri
Petropoulos, Christos J.
Pogson, Grant H.
Alexander, David L.
Perez, Gerardo
O’Rourke, Sara M.
Sinangil, Faruk
Robinson, Joseph
Conant, Marcus A.
Berman, Phillip W.
Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens
title Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens
title_full Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens
title_fullStr Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens
title_full_unstemmed Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens
title_short Ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of HIV vaccine immunogens
title_sort ancestral sequences from an elite neutralizer proximal to the development of neutralization resistance as a potential source of hiv vaccine immunogens
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457492/
https://www.ncbi.nlm.nih.gov/pubmed/30969970
http://dx.doi.org/10.1371/journal.pone.0213409
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