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1.
Cell ; 161(6): 1280-92, 2015 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-26004070

RESUMEN

The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and VH-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by VH-gene-restricted ontogenies.


Asunto(s)
Anticuerpos Neutralizantes/química , Anticuerpos Antivirales/química , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/fisiología , Secuencia de Aminoácidos , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/metabolismo , Linfocitos B/inmunología , Antígenos CD4/metabolismo , Regiones Determinantes de Complementariedad , Epítopos de Linfocito B , Proteína gp120 de Envoltorio del VIH/inmunología , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Alineación de Secuencia
2.
Immunity ; 39(2): 245-58, 2013 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-23911655

RESUMEN

Antibodies of the VRC01 class neutralize HIV-1, arise in diverse HIV-1-infected donors, and are potential templates for an effective HIV-1 vaccine. However, the stochastic processes that generate repertoires in each individual of >10(12) antibodies make elicitation of specific antibodies uncertain. Here we determine the ontogeny of the VRC01 class by crystallography and next-generation sequencing. Despite antibody-sequence differences exceeding 50%, antibody-gp120 cocrystal structures reveal VRC01-class recognition to be remarkably similar. B cell transcripts indicate that VRC01-class antibodies require few specific genetic elements, suggesting that naive-B cells with VRC01-class features are generated regularly by recombination. Virtually all of these fail to mature, however, with only a few-likely one-ancestor B cell expanding to form a VRC01-class lineage in each donor. Developmental similarities in multiple donors thus reveal the generation of VRC01-class antibodies to be reproducible in principle, thereby providing a framework for attempts to elicit similar antibodies in the general population.


Asunto(s)
Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/inmunología , Anticuerpos Anti-VIH/genética , Anticuerpos Anti-VIH/inmunología , VIH-1/inmunología , Secuencia de Aminoácidos , Anticuerpos Neutralizantes/inmunología , Linfocitos B/inmunología , Secuencia de Bases , Anticuerpos ampliamente neutralizantes , Cristalografía por Rayos X , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , Humanos , Leucocitos Mononucleares , Datos de Secuencia Molecular , Análisis de Secuencia de ADN
3.
J Virol ; 86(6): 3393-7, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22258252

RESUMEN

HIV-1 neutralizing monoclonal antibodies (MAbs) define key targets for vaccine development and are being considered for passive prevention of infection. We analyzed the interaction of MAbs to two independent epitopes on the viral envelope glycoprotein. Potently neutralizing MAbs to the CD4 binding site and V1V2 region displayed no in vitro cross-competition and displayed additive, though not synergistic, neutralization activity. Predicted neutralization coverage of a combination of two MAbs reached 97% on a 208-isolate panel.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Epítopos/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , Humanos
4.
J Virol ; 86(10): 5844-56, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22419808

RESUMEN

The monoclonal antibody (MAb) VRC01 was isolated from a slowly progressing HIV-1-infected donor and was shown to neutralize diverse HIV-1 strains by binding to the conserved CD4 binding site (CD4bs) of gp120. To better understand the virologic factors associated with such antibody development, we characterized HIV-1 envelope (Env) variants from this donor and five other donors who developed broadly neutralizing antibodies. A total of 473 env sequences were obtained by single-genome amplification, and 100 representative env clones were expressed and tested for entry and neutralization sensitivity. While VRC01 neutralizes about 90% of the genetically diverse heterologous HIV-1 strains tested, only selective archival Env variants from the VRC01 donor were sensitive to VRC01 and all of the Env variants derived from the donor plasma were resistant, indicating strong antibody-based selection pressure. Despite their resistance to this broadly reactive MAb that partially mimics CD4, all Env variants required CD4 for entry. Three other CD4bs MAbs from the same donor were able to neutralize some VRC01 escape variants, suggesting that CD4bs antibodies continued to evolve in response to viral escape. We also observed a relatively high percentage of VRC01-resistant Env clones in the plasma of four of five additional broadly neutralizing donors, suggesting the presence of CD4bs-directed neutralizing antibodies in these donors. In total, these data indicate that the CD4bs-directed neutralizing antibodies exert ongoing selection pressure on the conserved CD4bs epitope of HIV-1 Env.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Antígenos CD4/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Selección Genética , Secuencia de Aminoácidos , Sitios de Unión , Antígenos CD4/química , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Secuencia Conservada , Proteína gp120 de Envoltorio del VIH/química , Infecciones por VIH/inmunología , VIH-1/química , VIH-1/clasificación , VIH-1/genética , Humanos , Datos de Secuencia Molecular , Filogenia , Alineación de Secuencia
5.
Adv Mater ; 27(14): 2384-9, 2015 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-25688855

RESUMEN

A series of well-ordered, 3D gradient porous interconnected network surfaces composed of micro-nano hierarchical geometries is constructed on a copper wire. A continuous gas film can be trapped around its interface in an aqueous medium acting as an effective channel for gas transportation. Driving by the difference of the Laplace pressure, gas bubbles can be transported spontaneously and directionally.


Asunto(s)
Biomimética/métodos , Gases/química , Agua/química , Cobre/química , Interacciones Hidrofóbicas e Hidrofílicas , Movimiento (Física) , Porosidad , Propiedades de Superficie
6.
Science ; 333(6049): 1593-602, 2011 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-21835983

RESUMEN

Antibody VRC01 is a human immunoglobulin that neutralizes about 90% of HIV-1 isolates. To understand how such broadly neutralizing antibodies develop, we used x-ray crystallography and 454 pyrosequencing to characterize additional VRC01-like antibodies from HIV-1-infected individuals. Crystal structures revealed a convergent mode of binding for diverse antibodies to the same CD4-binding-site epitope. A functional genomics analysis of expressed heavy and light chains revealed common pathways of antibody-heavy chain maturation, confined to the IGHV1-2*02 lineage, involving dozens of somatic changes, and capable of pairing with different light chains. Broadly neutralizing HIV-1 immunity associated with VRC01-like antibodies thus involves the evolution of antibodies to a highly affinity-matured state required to recognize an invariant viral structure, with lineages defined from thousands of sequences providing a genetic roadmap of their development.


Asunto(s)
Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/inmunología , Evolución Molecular , Anticuerpos Anti-VIH/química , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , VIH-1/inmunología , Vacunas contra el SIDA , Secuencia de Aminoácidos , Anticuerpos Neutralizantes/genética , Anticuerpos Neutralizantes/aislamiento & purificación , Afinidad de Anticuerpos , Especificidad de Anticuerpos , Secuencia de Bases , Sitios de Unión , Sitios de Unión de Anticuerpos , Antígenos CD4/metabolismo , Regiones Determinantes de Complementariedad/genética , Cristalografía por Rayos X , Epítopos , Genes de las Cadenas Pesadas de las Inmunoglobulinas , Anticuerpos Anti-VIH/genética , Anticuerpos Anti-VIH/aislamiento & purificación , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/inmunología , VIH-1/química , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Fragmentos Fab de Inmunoglobulinas/química , Fragmentos Fab de Inmunoglobulinas/inmunología , Cadenas Pesadas de Inmunoglobulina/química , Cadenas Pesadas de Inmunoglobulina/inmunología , Cadenas J de Inmunoglobulina/genética , Cadenas Ligeras de Inmunoglobulina/química , Cadenas Ligeras de Inmunoglobulina/inmunología , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Análisis de Secuencia de ADN
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