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1.
Cell Rep ; 35(1): 108937, 2021 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-33826898

RESUMEN

Soluble "SOSIP"-stabilized envelope (Env) trimers are promising HIV-vaccine immunogens. However, they induce high-titer responses against the glycan-free trimer base, which is occluded on native virions. To delineate the effect on base responses of priming with immunogens targeting the fusion peptide (FP) site of vulnerability, here, we quantify the prevalence of trimer-base antibody responses in 49 non-human primates immunized with various SOSIP-stabilized Env trimers and FP-carrier conjugates. Trimer-base responses account for ∼90% of the overall trimer response in animals immunized with trimer only, ∼70% in animals immunized with a cocktail of SOSIP trimer and FP conjugate, and ∼30% in animals primed with FP conjugates before trimer immunization. Notably, neutralization breadth in FP-conjugate-primed animals correlates inversely with trimer-base responses. Our data provide methods to quantify the prevalence of trimer-base responses and reveal that FP-conjugate priming, either alone or as part of a cocktail, can reduce the trimer-base response and improve the neutralization outcome.


Asunto(s)
Formación de Anticuerpos/inmunología , VIH-1/inmunología , Péptidos/inmunología , Multimerización de Proteína , Proteínas Recombinantes de Fusión/metabolismo , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Femenino , Humanos , Inmunización , Fragmentos Fab de Inmunoglobulinas/inmunología , Macaca mulatta , Masculino , Modelos Biológicos
2.
Cell Rep ; 32(5): 107981, 2020 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-32755575

RESUMEN

The HIV fusion peptide (FP) is a promising vaccine target. FP-directed monoclonal antibodies from vaccinated macaques have been identified that neutralize up to ∼60% of HIV strains; these vaccinations, however, have involved ∼1 year with an extended neutralization-eclipse phase without measurable serum neutralization. Here, in 32 macaques, we test seven vaccination regimens, each comprising multiple immunizations of FP-carrier conjugates and HIV envelope (Env) trimers. Comparisons of vaccine regimens reveal FP-carrier conjugates to imprint cross-clade neutralizing responses and a cocktail of FP conjugate and Env trimer to elicit the earliest broad responses. We identify a signature, appearing as early as week 6 and involving the frequency of B cells recognizing both FP and Env trimer, predictive of vaccine-elicited breadth ∼1 year later. Immune monitoring of B cells in response to vaccination can thus enable vaccine insights even in the absence of serum neutralization, here identifying FP imprinting, cocktail approach, and early signature as means to improve FP-directed vaccine responses.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Linfocitos B/inmunología , Anticuerpos Anti-VIH/inmunología , Monitorización Inmunológica , Péptidos/inmunología , Proteínas Recombinantes de Fusión/inmunología , Vacunas contra el SIDA/inmunología , Animales , Antígenos VIH/inmunología , Infecciones por VIH/inmunología , Hemocianinas/metabolismo , Inmunización , Macaca mulatta , Masculino , Polisacáridos/metabolismo , Multimerización de Proteína , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología
3.
Cell ; 178(3): 567-584.e19, 2019 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-31348886

RESUMEN

The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization.


Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Péptidos/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/clasificación , Linfocitos B/citología , Linfocitos B/metabolismo , Cristalografía por Rayos X , Femenino , Células HEK293 , Anticuerpos Anti-VIH/química , Anticuerpos Anti-VIH/clasificación , VIH-1/metabolismo , Humanos , Macaca mulatta , Masculino , Péptidos/química , Estructura Terciaria de Proteína , Productos del Gen env del Virus de la Inmunodeficiencia Humana/química , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo
4.
Nat Commun ; 6: 7712, 2015 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-26218507

RESUMEN

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development. Efforts focused solely on the receptor-binding domain (RBD) of the viral Spike (S) glycoprotein may not optimize neutralizing antibody (NAb) responses. Here we show that immunogens based on full-length S DNA and S1 subunit protein elicit robust serum-neutralizing activity against several MERS-CoV strains in mice and non-human primates. Serological analysis and isolation of murine monoclonal antibodies revealed that immunization elicits NAbs to RBD and, non-RBD portions of S1 and S2 subunit. Multiple neutralization mechanisms were demonstrated by solving the atomic structure of a NAb-RBD complex, through sequencing of neutralization escape viruses and by constructing MERS-CoV S variants for serological assays. Immunization of rhesus macaques confers protection against MERS-CoV-induced radiographic pneumonia, as assessed using computerized tomography, supporting this strategy as a promising approach for MERS-CoV vaccine development.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Infecciones por Coronavirus/prevención & control , ADN Viral/inmunología , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas de ADN/inmunología , Vacunas Virales/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Femenino , Células HEK293 , Humanos , Inmunoglobulina G/inmunología , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos BALB C
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