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Title

Guiding the humoral response against HIV-1 toward a MPER adjacent region by immunization with a VLP-formulated antibody-selected envelope variant

AuthorsBeltran-Pavez, Carolina; Ferreira, Carolina B.; Merino-Mansilla, Alberto; Fabra-García, Amanda; Casadellà, Maria; Noguera-Julián, Marc; Paredes, Roger; Olvera, Àlex; Haro Villar, Isabel ; Brander, Christian; García, Felipe; Gatell, José María A.; Yuste, Eloísa; Sánchez-Merino, Víctor
KeywordsVaccine strategies
HIV-1
VLP-formulated antibody-selected envelope variant
Issue DateDec-2018
PublisherPublic Library of Science
CitationPLoS ONE 13 (12): e0208345 (2018)
AbstractPreventive 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. © 2018 Beltran-Pavez et al. 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 credited.
Publisher version (URL)https://doi.org/10.1371/journal.pone.0208345
URIhttp://hdl.handle.net/10261/173897
DOIhttp://dx.doi.org/10.1371/journal.pone.0208345
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S1 Table. Primer sequences used for in vitro random mutagenesis, nested RT-PCR HIV env amplification and sequencing (standard and deep-sequencing)..docxS1 Table. Primer sequences used for in vitro random mutagenesis, nested RT-PCR HIV env amplification and sequencing (standard and deep-sequencing).14,82 kBMicrosoft Word XMLView/Open
S2 Table. Neutralization profile of AC10_29 recombinant virus (Clade B, tier 2) used as template for generating the virion library.docxS2 Table. Neutralization profile of AC10_29 recombinant virus (Clade B, tier 2) used as template for generating the virion library16,03 kBMicrosoft Word XMLView/Open
S3 Table. Comparison of mutation percentages within the same envelope regions (amplicons) in standard and deep-sequencing before and after selection..docxS3 Table. Comparison of mutation percentages within the same envelope regions (amplicons) in standard and deep-sequencing before and after selection.15,75 kBMicrosoft Word XMLView/Open
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