Cargando…

Selected HIV-1 Env Trimeric Formulations Act as Potent Immunogens in a Rabbit Vaccination Model

BACKGROUND: Ten to 30% of HIV-1 infected subjects develop broadly neutralizing antibodies (bNAbs) during chronic infection. We hypothesized that immunizing rabbits with viral envelope glycoproteins (Envs) from these patients may induce bNAbs, when formulated as a trimeric protein and in the presence...

Descripción completa

Detalles Bibliográficos
Autores principales: Heyndrickx, Leo, Stewart-Jones, Guillaume, Jansson, Marianne, Schuitemaker, Hanneke, Bowles, Emma, Buonaguro, Luigi, Grevstad, Berit, Vinner, Lasse, Vereecken, Katleen, Parker, Joe, Ramaswamy, Meghna, Biswas, Priscilla, Vanham, Guido, Scarlatti, Gabriella, Fomsgaard, Anders
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759472/
https://www.ncbi.nlm.nih.gov/pubmed/24023951
http://dx.doi.org/10.1371/journal.pone.0074552
_version_ 1782477268184989696
author Heyndrickx, Leo
Stewart-Jones, Guillaume
Jansson, Marianne
Schuitemaker, Hanneke
Bowles, Emma
Buonaguro, Luigi
Grevstad, Berit
Vinner, Lasse
Vereecken, Katleen
Parker, Joe
Ramaswamy, Meghna
Biswas, Priscilla
Vanham, Guido
Scarlatti, Gabriella
Fomsgaard, Anders
author_facet Heyndrickx, Leo
Stewart-Jones, Guillaume
Jansson, Marianne
Schuitemaker, Hanneke
Bowles, Emma
Buonaguro, Luigi
Grevstad, Berit
Vinner, Lasse
Vereecken, Katleen
Parker, Joe
Ramaswamy, Meghna
Biswas, Priscilla
Vanham, Guido
Scarlatti, Gabriella
Fomsgaard, Anders
author_sort Heyndrickx, Leo
collection PubMed
description BACKGROUND: Ten to 30% of HIV-1 infected subjects develop broadly neutralizing antibodies (bNAbs) during chronic infection. We hypothesized that immunizing rabbits with viral envelope glycoproteins (Envs) from these patients may induce bNAbs, when formulated as a trimeric protein and in the presence of an adjuvant. METHODS: Based on in vitro neutralizing activity in serum, patients with bNAbs were selected for cloning of their HIV-1 Env. Seven stable soluble trimeric gp140 proteins were generated from sequences derived from four adults and two children infected with either clade A or B HIV-1. From one of the clade A Envs both the monomeric and trimeric Env were produced for comparison. Rabbits were immunized with soluble gp120 or trimeric gp140 proteins in combination with the adjuvant dimethyl dioctadecyl ammonium/trehalose dibehenate (CAF01). Env binding in rabbit immune serum was determined using ELISAs based on gp120-IIIB protein. Neutralizing activity of IgG purified from rabbit immune sera was measured with the pseudovirus-TZMbl assay and a PBMC-based neutralization assay for selected experiments. RESULTS: It was initially established that gp140 trimers induce better antibody responses over gp120 monomers and that the adjuvant CAF01 was necessary for such strong responses. Gp140 trimers, based on HIV-1 variants from patients with bNAbs, were able to elicit both gp120(IIIB) specific IgG and NAbs to Tier 1 viruses of different subtypes. Potency of NAbs closely correlated with titers, and an gp120-binding IgG titer above a threshold of 100,000 was predictive of neutralization capability. Finally, peptide inhibition experiments showed that a large fraction of the neutralizing IgG was directed against the gp120 V3 region. CONCLUSIONS: Our results indicate that the strategy of reverse immunology based on selected Env sequences is promising when immunogens are delivered as stabilized trimers in CAF01 adjuvant and that the rabbit is a valuable model for HIV vaccine studies.
format Online
Article
Text
id pubmed-3759472
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-37594722013-09-10 Selected HIV-1 Env Trimeric Formulations Act as Potent Immunogens in a Rabbit Vaccination Model Heyndrickx, Leo Stewart-Jones, Guillaume Jansson, Marianne Schuitemaker, Hanneke Bowles, Emma Buonaguro, Luigi Grevstad, Berit Vinner, Lasse Vereecken, Katleen Parker, Joe Ramaswamy, Meghna Biswas, Priscilla Vanham, Guido Scarlatti, Gabriella Fomsgaard, Anders PLoS One Research Article BACKGROUND: Ten to 30% of HIV-1 infected subjects develop broadly neutralizing antibodies (bNAbs) during chronic infection. We hypothesized that immunizing rabbits with viral envelope glycoproteins (Envs) from these patients may induce bNAbs, when formulated as a trimeric protein and in the presence of an adjuvant. METHODS: Based on in vitro neutralizing activity in serum, patients with bNAbs were selected for cloning of their HIV-1 Env. Seven stable soluble trimeric gp140 proteins were generated from sequences derived from four adults and two children infected with either clade A or B HIV-1. From one of the clade A Envs both the monomeric and trimeric Env were produced for comparison. Rabbits were immunized with soluble gp120 or trimeric gp140 proteins in combination with the adjuvant dimethyl dioctadecyl ammonium/trehalose dibehenate (CAF01). Env binding in rabbit immune serum was determined using ELISAs based on gp120-IIIB protein. Neutralizing activity of IgG purified from rabbit immune sera was measured with the pseudovirus-TZMbl assay and a PBMC-based neutralization assay for selected experiments. RESULTS: It was initially established that gp140 trimers induce better antibody responses over gp120 monomers and that the adjuvant CAF01 was necessary for such strong responses. Gp140 trimers, based on HIV-1 variants from patients with bNAbs, were able to elicit both gp120(IIIB) specific IgG and NAbs to Tier 1 viruses of different subtypes. Potency of NAbs closely correlated with titers, and an gp120-binding IgG titer above a threshold of 100,000 was predictive of neutralization capability. Finally, peptide inhibition experiments showed that a large fraction of the neutralizing IgG was directed against the gp120 V3 region. CONCLUSIONS: Our results indicate that the strategy of reverse immunology based on selected Env sequences is promising when immunogens are delivered as stabilized trimers in CAF01 adjuvant and that the rabbit is a valuable model for HIV vaccine studies. Public Library of Science 2013-09-02 /pmc/articles/PMC3759472/ /pubmed/24023951 http://dx.doi.org/10.1371/journal.pone.0074552 Text en © 2013 Heyndrickx 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Heyndrickx, Leo
Stewart-Jones, Guillaume
Jansson, Marianne
Schuitemaker, Hanneke
Bowles, Emma
Buonaguro, Luigi
Grevstad, Berit
Vinner, Lasse
Vereecken, Katleen
Parker, Joe
Ramaswamy, Meghna
Biswas, Priscilla
Vanham, Guido
Scarlatti, Gabriella
Fomsgaard, Anders
Selected HIV-1 Env Trimeric Formulations Act as Potent Immunogens in a Rabbit Vaccination Model
title Selected HIV-1 Env Trimeric Formulations Act as Potent Immunogens in a Rabbit Vaccination Model
title_full Selected HIV-1 Env Trimeric Formulations Act as Potent Immunogens in a Rabbit Vaccination Model
title_fullStr Selected HIV-1 Env Trimeric Formulations Act as Potent Immunogens in a Rabbit Vaccination Model
title_full_unstemmed Selected HIV-1 Env Trimeric Formulations Act as Potent Immunogens in a Rabbit Vaccination Model
title_short Selected HIV-1 Env Trimeric Formulations Act as Potent Immunogens in a Rabbit Vaccination Model
title_sort selected hiv-1 env trimeric formulations act as potent immunogens in a rabbit vaccination model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759472/
https://www.ncbi.nlm.nih.gov/pubmed/24023951
http://dx.doi.org/10.1371/journal.pone.0074552
work_keys_str_mv AT heyndrickxleo selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT stewartjonesguillaume selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT janssonmarianne selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT schuitemakerhanneke selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT bowlesemma selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT buonaguroluigi selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT grevstadberit selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT vinnerlasse selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT vereeckenkatleen selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT parkerjoe selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT ramaswamymeghna selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT biswaspriscilla selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT vanhamguido selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT scarlattigabriella selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT fomsgaardanders selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel
AT selectedhiv1envtrimericformulationsactaspotentimmunogensinarabbitvaccinationmodel