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dc.contributor.authorPejawar Gaddy, Sharmila
dc.contributor.authorKovacs, J.
dc.contributor.authorBarouch, D.
dc.contributor.authorChen, B.
dc.contributor.authorIrvine, Darrell J.
dc.date.accessioned2013-01-28T19:56:58Z
dc.date.available2013-01-28T19:56:58Z
dc.date.issued2012-09
dc.date.submitted2012-09
dc.identifier.issn1742-4690
dc.identifier.urihttp://hdl.handle.net/1721.1/76620
dc.description.abstractBackground: Immunization strategies that elicit antibodies capable of neutralizing diverse strains of the virus will likely be an important part of a successful vaccine against HIV. The envelope trimer is the only neutralizing target on the virus, and strategies to promote durable, high avidity antibody responses against the native intact trimer structure are lacking. We recently developed chemically-crosslinked lipid nanocapsules as carriers of molecular adjuvants and encapsulated or surface-displayed antigens, which promote follicular helper T-cell responses and elicited high-avidity, durable antibody responses to a candidate malaria antigen (Moon et al. Nat. Mater. 10 243 (2011); Moon et al. PNAS 109 1080 (2012)). Methods: To apply this system to the delivery of HIV antigens, we developed a strategy to anchor recombinant envelope trimers to the surfaces of these particles under conditions preserving the antigenic integrity of the trimers, allowing multivalent display of these immunogens for immunization. To anchor trimers in their native orientation, gp140 trimers with terminal his-tags were anchored to the surface of lipid nanocapsules via Ni-NTA-functionalized lipids. Results: Owing to their significant size (409 kDa) and heavy glycosylation, we found that liquid-ordered and/or gel-phase lipid compositions were required to stably anchor trimers to particle membranes. Trimer-loaded nanocapsules carrying monophosphoryl lipid A elicited durable antibody responses with titers comparable to a Complete Freund’s Adjuvant (CFA)-like emulsion in mice, without the toxic inflammation associated with the latter adjuvant. Further, nanocapsules elicited strong helper T-cell responses associated with a steadily increasing avidity of trimer-binding antibody over 90 days, which was not replicated by other adjuvants. Conclusion: These results suggest that nanoparticles displaying HIV trimers in an oriented, multivalent presentation can promote key aspects of the humoral response against Env immunogens.en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (AI095109)en_US
dc.description.sponsorshipMassachusetts Institute of Technology. Ragon Institute of MGH, MIT, and Harvarden_US
dc.language.isoen_US
dc.publisherBioMed Central Ltd.en_US
dc.relation.isversionofhttp://dx.doi.org/10.1186/1742-4690-9-s2-o10en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by/2.0en_US
dc.sourceBioMed Centralen_US
dc.titleDesign of lipid nanoparticle delivery agents for multivalent display of recombinant Env trimers in HIV vaccinationen_US
dc.typeArticleen_US
dc.identifier.citationPejawar-Gaddy, S et al. “Design of Lipid Nanoparticle Delivery Agents for Multivalent Display of Recombinant Env Trimers in HIV Vaccination.” Retrovirology 9.Suppl 2 (2012): O10.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Materials Science and Engineeringen_US
dc.contributor.mitauthorPejawar Gaddy, Sharmila
dc.contributor.mitauthorIrvine, Darrell J.
dc.relation.journalRetrovirologyen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsPejawar-Gaddy, S; Kovacs, J; Barouch, D; Chen, B; Irvine, Den
mit.licensePUBLISHER_CCen_US
mit.metadata.statusComplete


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