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1.
Immunity ; 50(3): 677-691.e13, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30876875

RESUMO

Lineage-based vaccine design is an attractive approach for eliciting broadly neutralizing antibodies (bNAbs) against HIV-1. However, most bNAb lineages studied to date have features indicative of unusual recombination and/or development. From an individual in the prospective RV217 cohort, we identified three lineages of bNAbs targeting the membrane-proximal external region (MPER) of the HIV-1 envelope. Antibodies RV217-VRC42.01, -VRC43.01, and -VRC46.01 used distinct modes of recognition and neutralized 96%, 62%, and 30%, respectively, of a 208-strain virus panel. All three lineages had modest levels of somatic hypermutation and normal antibody-loop lengths and were initiated by the founder virus MPER. The broadest lineage, VRC42, was similar to the known bNAb 4E10. A multimeric immunogen based on the founder MPER activated B cells bearing the unmutated common ancestor of VRC42, with modest maturation of early VRC42 intermediates imparting neutralization breadth. These features suggest that VRC42 may be a promising template for lineage-based vaccine design.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Vacinas contra a AIDS/imunologia , Sequência de Aminoácidos , Linfócitos B/imunologia , Linhagem Celular , Células HEK293 , Infecções por HIV/imunologia , Humanos , Leucócitos Mononucleares , Estudos Longitudinais
2.
R I Med J (2013) ; 107(9): 10-14, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39186394

RESUMO

Mucoceles of the paranasal sinuses are benign, expansile lesions that develop secondary to sinus ostia obstruction. Presenting signs and symptoms vary widely but frequently include frontal headache and swelling, as well as visual changes and globe displacement depending on orbital involvement in the case of frontal sinus mucoceles. Given the potential for orbital or intracranial involvement, urgent imaging with computed tomography (CT) is important for patients with symptoms concerning for a frontal sinus mucocele. Definitive treatment is surgical. In this article, we report a case of a 50-year-old male who presented to a primary care clinic with a painful forehead mass, found to have a frontal sinus mucocele with erosion through the frontal bone that was eventually treated surgically. We also summarize presenting signs and symptoms of frontal mucoceles reported in the literature as these are important for clinicians to be familiar with, considering the potential emergent complications.


Assuntos
Testa , Seio Frontal , Mucocele , Tomografia Computadorizada por Raios X , Humanos , Masculino , Mucocele/diagnóstico por imagem , Mucocele/complicações , Mucocele/diagnóstico , Mucocele/cirurgia , Pessoa de Meia-Idade , Seio Frontal/diagnóstico por imagem , Seio Frontal/patologia , Doença Crônica , Doenças dos Seios Paranasais/diagnóstico por imagem , Doenças dos Seios Paranasais/complicações , Doenças dos Seios Paranasais/cirurgia , Sinusite Frontal/complicações , Sinusite Frontal/diagnóstico por imagem
3.
Sci Rep ; 12(1): 17876, 2022 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-36284200

RESUMO

The broadly neutralizing antibody (bNAb) CAP256-VRC26.25 has exceptional potency against HIV-1 and has been considered for clinical use. During the characterization and production of this bNAb, we observed several unusual features. First, the antibody appeared to adhere to pipette tips, requiring tips to be changed during serial dilution to accurately measure potency. Second, during production scale-up, proteolytic cleavage was discovered to target an extended heavy chain loop, which was attributed to a protease in spent medium from 2-week culture. To enable large scale production, we altered the site of cleavage via a single amino acid change, K100mA. The resultant antibody retained potency and breadth while avoiding protease cleavage. We also added the half-life extending mutation LS, which improved the in vivo persistence in animal models, but did not impact neutralization activity; we observed the same preservation of neutralization for bNAbs VRC01, N6, and PGDM1400 with LS on a 208-virus panel. The final engineered antibody, CAP256V2LS, retained the extraordinary neutralization potency of the parental antibody, had a favorable pharmacokinetic profile in animal models, and was negative in in vitro assessment of autoreactivity. CAP256V2LS has the requisite potency, developability and suitability for scale-up, allowing its advancement as a clinical candidate.


Assuntos
Infecções por HIV , HIV-1 , Animais , Anticorpos Amplamente Neutralizantes , Meia-Vida , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Peptídeo Hidrolases , Aminoácidos
4.
Cell Rep ; 31(4): 107583, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32348769

RESUMO

Structural and functional studies of HIV envelope glycoprotein (Env) as a transmembrane protein have long been complicated by challenges associated with inherent flexibility of the molecule and the membrane-embedded hydrophobic regions. Here, we present approaches for incorporating full-length, wild-type HIV-1 Env, as well as C-terminally truncated and stabilized versions, into lipid assemblies, providing a modular platform for Env structural studies by single particle electron microscopy. We reconstitute a full-length Env clone into a nanodisc, complex it with a membrane-proximal external region (MPER) targeting antibody 10E8, and structurally define the full quaternary epitope of 10E8 consisting of lipid, MPER, and ectodomain contacts. By aligning this and other Env-MPER antibody complex reconstructions with the lipid bilayer, we observe evidence of Env tilting as part of the neutralization mechanism for MPER-targeting antibodies. We also adapt the platform toward vaccine design purposes by introducing stabilizing mutations that allow purification of unliganded Env with a peptidisc scaffold.


Assuntos
Proteína gp41 do Envelope de HIV/genética , HIV-1/genética , Bicamadas Lipídicas/metabolismo , Humanos
5.
Nat Commun ; 9(1): 4136, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30297708

RESUMO

The developmental pathways of broadly neutralizing antibodies (bNAbs) against HIV are of great importance for the design of immunogens that can elicit protective responses. Here we show the maturation features of the HIV-neutralizing anti-V1V2 VRC26 lineage by simultaneously sequencing the exon together with the downstream intron of VRC26 members. Using the mutational landscapes of both segments and the selection-free nature of the intron region, we identify multiple events of amino acid mutational convergence in the complementarity-determining region 3 (CDR3) of VRC26 members, and determine potential intermediates with diverse CDR3s to a late stage bNAb from 2 years prior to its isolation. Moreover, we functionally characterize the earliest neutralizing intermediates with critical CDR3 mutations, with some emerging only 14 weeks after initial lineage detection and containing only ~6% V gene mutations. Our results thus underscore the utility of analyzing exons and introns simultaneously for studying antibody maturation and repertoire selection.


Assuntos
Anticorpos Neutralizantes/imunologia , Éxons/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Íntrons/imunologia , Vacinas contra a AIDS/genética , Vacinas contra a AIDS/imunologia , Anticorpos Neutralizantes/genética , Epitopos/genética , Epitopos/imunologia , Éxons/genética , Anticorpos Anti-HIV/genética , HIV-1/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Íntrons/genética , Mutação
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