Guiding the humoral response against HIV-1 toward a MPER adjacent region by immunization with a VLP-formulated antibody-selected envelope variant.
Preventive HIV-1 vaccine strategies rely on the elicitation of broadly neutralizing antibody (bNAb) responses, but their induction in vivo by vaccination remains challenging. Considering that the ability of an epitope to elicit effective humoral immunity depends on its exposure on the virion, we hav...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0208345 |
| _version_ | 1818677817775226880 |
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| author | Carolina Beltran-Pavez Carolina B Ferreira Alberto Merino-Mansilla Amanda Fabra-Garcia Maria Casadella Marc Noguera-Julian Roger Paredes Alex Olvera Isabel Haro Christian Brander Felipe Garcia Jose M Gatell Eloisa Yuste Victor Sanchez-Merino |
| author_facet | Carolina Beltran-Pavez Carolina B Ferreira Alberto Merino-Mansilla Amanda Fabra-Garcia Maria Casadella Marc Noguera-Julian Roger Paredes Alex Olvera Isabel Haro Christian Brander Felipe Garcia Jose M Gatell Eloisa Yuste Victor Sanchez-Merino |
| author_sort | Carolina Beltran-Pavez |
| collection | DOAJ |
| description | Preventive HIV-1 vaccine strategies rely on the elicitation of broadly neutralizing antibody (bNAb) responses, but their induction in vivo by vaccination remains challenging. Considering that the ability of an epitope to elicit effective humoral immunity depends on its exposure on the virion, we have used a reverse genetics approach to select variants from an HIV-1 AC10_29 randomly mutated envelope library that showed increased affinity for a selected bNAb (4E10 bNAb targeting the HIV-1 MPER region). Isolated envelope sequences were analyzed by deep-sequencing showing a small number of dominant changes, including the loss of four potential N-linked glycosylation sites and disruption of the V1/V2 loop. Accordingly, the dominant variant (LR1-C1), showed not only increased affinity for MPER bNAbs 4E10 and 2F5, but also higher affinity for an additional antibody targeting the V3 loop (447-52D) that could be a consequence of an open conformation tier 1-like Env. Furthermore, the amino acids specific for the selected variant are associated with an increased sensitivity for 4E10 and 2F5 antibodies. In vivo studies showed that sera from mice immunized with LR1-C1 viruses possessed an improved neutralizing activity compared to the wild-type AC10_29 env. While Virus Like Particles (VLPs) carrying this envelope were unable to induce detectable neutralizing activity in immunized rabbits, one animal showed antibody response to the 4E10-proximal region. Our data establish a novel approach that has the potential to yield HIV envelope immunogen sequences that direct antibody responses to specific envelope regions. |
| first_indexed | 2024-12-17T09:05:24Z |
| format | Article |
| id | doaj.art-21101a16974d423b9db3e415e5522e6b |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-17T09:05:24Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-21101a16974d423b9db3e415e5522e6b2022-12-21T21:55:31ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-011312e020834510.1371/journal.pone.0208345Guiding the humoral response against HIV-1 toward a MPER adjacent region by immunization with a VLP-formulated antibody-selected envelope variant.Carolina Beltran-PavezCarolina B FerreiraAlberto Merino-MansillaAmanda Fabra-GarciaMaria CasadellaMarc Noguera-JulianRoger ParedesAlex OlveraIsabel HaroChristian BranderFelipe GarciaJose M GatellEloisa YusteVictor Sanchez-MerinoPreventive HIV-1 vaccine strategies rely on the elicitation of broadly neutralizing antibody (bNAb) responses, but their induction in vivo by vaccination remains challenging. Considering that the ability of an epitope to elicit effective humoral immunity depends on its exposure on the virion, we have used a reverse genetics approach to select variants from an HIV-1 AC10_29 randomly mutated envelope library that showed increased affinity for a selected bNAb (4E10 bNAb targeting the HIV-1 MPER region). Isolated envelope sequences were analyzed by deep-sequencing showing a small number of dominant changes, including the loss of four potential N-linked glycosylation sites and disruption of the V1/V2 loop. Accordingly, the dominant variant (LR1-C1), showed not only increased affinity for MPER bNAbs 4E10 and 2F5, but also higher affinity for an additional antibody targeting the V3 loop (447-52D) that could be a consequence of an open conformation tier 1-like Env. Furthermore, the amino acids specific for the selected variant are associated with an increased sensitivity for 4E10 and 2F5 antibodies. In vivo studies showed that sera from mice immunized with LR1-C1 viruses possessed an improved neutralizing activity compared to the wild-type AC10_29 env. While Virus Like Particles (VLPs) carrying this envelope were unable to induce detectable neutralizing activity in immunized rabbits, one animal showed antibody response to the 4E10-proximal region. Our data establish a novel approach that has the potential to yield HIV envelope immunogen sequences that direct antibody responses to specific envelope regions.https://doi.org/10.1371/journal.pone.0208345 |
| spellingShingle | Carolina Beltran-Pavez Carolina B Ferreira Alberto Merino-Mansilla Amanda Fabra-Garcia Maria Casadella Marc Noguera-Julian Roger Paredes Alex Olvera Isabel Haro Christian Brander Felipe Garcia Jose M Gatell Eloisa Yuste Victor Sanchez-Merino Guiding the humoral response against HIV-1 toward a MPER adjacent region by immunization with a VLP-formulated antibody-selected envelope variant. PLoS ONE |
| title | Guiding the humoral response against HIV-1 toward a MPER adjacent region by immunization with a VLP-formulated antibody-selected envelope variant. |
| title_full | Guiding the humoral response against HIV-1 toward a MPER adjacent region by immunization with a VLP-formulated antibody-selected envelope variant. |
| title_fullStr | Guiding the humoral response against HIV-1 toward a MPER adjacent region by immunization with a VLP-formulated antibody-selected envelope variant. |
| title_full_unstemmed | Guiding the humoral response against HIV-1 toward a MPER adjacent region by immunization with a VLP-formulated antibody-selected envelope variant. |
| title_short | Guiding the humoral response against HIV-1 toward a MPER adjacent region by immunization with a VLP-formulated antibody-selected envelope variant. |
| title_sort | guiding the humoral response against hiv 1 toward a mper adjacent region by immunization with a vlp formulated antibody selected envelope variant |
| url | https://doi.org/10.1371/journal.pone.0208345 |
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