Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30
Filtrar
1.
Nature ; 561(7723): 406-410, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30202088

RESUMEN

Understanding the determinants of broadly neutralizing antibody (bNAb) evolution is crucial for the development of bNAb-based HIV vaccines1. Despite emerging information on cofactors that promote bNAb evolution in natural HIV-1 infections, in which the induction of bNAbs is genuinely rare2, information on the impact of the infecting virus strain on determining the breadth and specificity of the antibody responses to HIV-1 is lacking. Here we analyse the influence of viral antigens in shaping antibody responses in humans. We call the ability of a virus strain to induce similar antibody responses across different hosts its antibody-imprinting capacity, which from an evolutionary biology perspective corresponds to the viral heritability of the antibody responses. Analysis of 53 measured parameters of HIV-1-binding and neutralizing antibody responses in a cohort of 303 HIV-1 transmission pairs (individuals who harboured highly related HIV-1 strains and were putative direct transmission partners or members of an HIV-1 transmission chain) revealed that the effect of the infecting virus on the outcome of the bNAb response is moderate in magnitude but highly significant. We introduce the concept of bNAb-imprinting viruses and provide evidence for the existence of such viruses in a systematic screening of our cohort. The bNAb-imprinting capacity can be substantial, as indicated by a transmission pair with highly similar HIV-1 antibody responses and strong bNAb activity. Identification of viruses that have bNAb-imprinting capacities and their characterization may thus provide the potential to develop lead immunogens.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/clasificación , VIH-1/inmunología , Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/análisis , Femenino , Anticuerpos Anti-VIH/análisis , Infecciones por VIH/transmisión , VIH-1/aislamiento & purificación , Humanos , Masculino
2.
PLoS Pathog ; 14(1): e1006825, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29370298

RESUMEN

Broadly neutralizing antibodies (bnAbs) to HIV-1 can evolve after years of an iterative process of virus escape and antibody adaptation that HIV-1 vaccine design seeks to mimic. To enable this, properties that render HIV-1 envelopes (Env) capable of eliciting bnAb responses need to be defined. Here, we followed the evolution of the V2 apex directed bnAb lineage VRC26 in the HIV-1 subtype C superinfected donor CAP256 to investigate the phenotypic changes of the virus populations circulating before and during the early phases of bnAb induction. Longitudinal viruses that evolved from the VRC26-resistant primary infecting (PI) virus, the VRC26-sensitive superinfecting (SU) virus and ensuing PI-SU recombinants revealed substantial phenotypic changes in Env, with a switch in Env properties coinciding with early resistance to VRC26. Decreased sensitivity of SU-like viruses to VRC26 was linked with reduced infectivity, altered entry kinetics and lower sensitivity to neutralization after CD4 attachment. VRC26 maintained neutralization activity against cell-associated CAP256 virus, indicating that escape through the cell-cell transmission route is not a dominant escape pathway. Reduced fitness of the early escape variants and sustained sensitivity in cell-cell transmission are both features that limit virus replication, thereby impeding rapid escape. This supports a scenario where VRC26 allowed only partial viral escape for a prolonged period, possibly increasing the time window for bnAb maturation. Collectively, our data highlight the phenotypic plasticity of the HIV-1 Env in evading bnAb pressure and the need to consider phenotypic traits when selecting and designing Env immunogens. Combinations of Env variants with differential phenotypic patterns and bnAb sensitivity, as we describe here for CAP256, may maximize the potential for inducing bnAb responses by vaccination.


Asunto(s)
Anticuerpos Neutralizantes/metabolismo , Formación de Anticuerpos , Epítopos/inmunología , Anticuerpos Anti-VIH/metabolismo , VIH-1/inmunología , Proteínas del Envoltorio Viral/inmunología , Secuencia de Aminoácidos , Variación Antigénica , Comunicación Celular/inmunología , Epítopos/química , Células HEK293 , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , Infecciones por VIH/virología , Humanos , Evasión Inmune , Pruebas de Neutralización , Fenotipo , Proteínas del Envoltorio Viral/química , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología
3.
PLoS Pathog ; 13(3): e1006255, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28264054

RESUMEN

A hallmark of HIV-1 infection is the continuously declining number of the virus' predominant target cells, activated CD4+ T cells. With diminishing CD4+ T cell levels, the capacity to utilize alternate cell types and receptors, including cells that express low CD4 receptor levels such as macrophages, thus becomes crucial. To explore evolutionary paths that allow HIV-1 to acquire a wider host cell range by infecting cells with lower CD4 levels, we dissected the evolution of the envelope-CD4 interaction under in vitro culture conditions that mimicked the decline of CD4high target cells, using a prototypic subtype B, R5-tropic strain. Adaptation to CD4low targets proved to severely alter envelope functions including trimer opening as indicated by a higher affinity to CD4 and loss in shielding against neutralizing antibodies. We observed a strikingly decreased infectivity on CD4high target cells, but sustained infectivity on CD4low targets, including macrophages. Intriguingly, the adaptation to CD4low targets altered the kinetic of the entry process, leading to rapid CD4 engagement and an extended transition time between CD4 and CCR5 binding during entry. This phenotype was also observed for certain central nervous system (CNS) derived macrophage-tropic viruses, highlighting that the functional perturbation we defined upon in vitro adaptation to CD4low targets occurs in vivo. Collectively, our findings suggest that CD4low adapted envelopes may exhibit severe deficiencies in entry fitness and shielding early in their evolution. Considering this, adaptation to CD4low targets may preferentially occur in a sheltered and immune-privileged environment such as the CNS to allow fitness restoring compensatory mutations to occur.


Asunto(s)
Antígenos CD4/metabolismo , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/virología , VIH-1/patogenicidad , Leucocitos Mononucleares/virología , Tropismo Viral/fisiología , Adaptación Fisiológica/fisiología , Separación Celular , Humanos , Macrófagos/virología , Internalización del Virus
4.
PLoS Pathog ; 11(7): e1004966, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26158270

RESUMEN

An increasing number of broadly neutralizing antibodies (bnAbs) are considered leads for HIV-1 vaccine development and novel therapeutics. Here, we systematically explored the capacity of bnAbs to neutralize HIV-1 prior to and post-CD4 engagement and to block HIV-1 cell-cell transmission. Cell-cell spread is known to promote a highly efficient infection with HIV-1 which can inflict dramatic losses in neutralization potency compared to free virus infection. Selection of bnAbs that are capable of suppressing HIV irrespective of the transmission mode therefore needs to be considered to ascertain their in vivo activity in therapeutic use and vaccines. Employing assay systems that allow for unambiguous discrimination between free virus and cell-cell transmission to T cells, we probed a panel of 16 bnAbs for their activity against 11 viruses from subtypes A, B and C during both transmission modes. Over a wide range of bnAb-virus combinations tested, inhibitory activity against HIV-1 cell-cell transmission was strongly decreased compared to free virus transmission. Activity loss varied considerably between virus strains and was inversely associated with neutralization of free virus spread for V1V2- and V3-directed bnAbs. In rare bnAb-virus combinations, inhibition for both transmission modes was comparable but no bnAb potently blocked cell-cell transmission across all probed virus strains. Mathematical analysis indicated an increased probability of bnAb resistance mutations to arise in cell-cell rather than free virus spread, further highlighting the need to block this pathway. Importantly, the capacity to efficiently neutralize prior to CD4 engagement correlated with the inhibition efficacy against free virus but not cell-cell transmitted virus. Pre-CD4 attachment activity proved strongest amongst CD4bs bnAbs and varied substantially for V3 and V1V2 loop bnAbs in a strain-dependent manner. In summary, bnAb activity against divergent viruses varied depending on the transmission mode and differed depending on the window of action during the entry process, underscoring that powerful combinations of bnAbs are needed for in vivo application.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , VIH-1/inmunología , Linfocitos T/virología , Humanos , Linfocitos T/inmunología
5.
Retrovirology ; 13(1): 62, 2016 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-27595568

RESUMEN

BACKGROUND: Mucosal HIV-1 transmission predominantly results in a single transmitted/founder (T/F) virus establishing infection in the new host despite the generally high genetic diversity of the transmitter virus population. To what extent HIV-1 transmission is a stochastic process or driven by selective forces that allow T/F viruses best to overcome bottlenecks in transmission has not been conclusively resolved. Building on prior investigations that suggest HIV-1 envelope (Env) features to contribute in the selection process during transmission, we compared phenotypic virus characteristics of nine HIV-1 subtype B transmission pairs, six men who have sex with men and three male-to-female transmission pairs. RESULTS: All recipients were identified early in acute infection and harbored based on extensive sequencing analysis a single T/F virus allowing a controlled analysis of virus properties in matched transmission pairs. Recipient and transmitter viruses from the closest time point to transmission showed no signs of selection for specific Env modifications such as variable loop length and glycosylation. Recipient viruses were resistant to circulating plasma antibodies of the transmitter and also showed no altered sensitivity to a large panel of entry inhibitors and neutralizing antibodies. The recipient virus did not consistently differ from the transmitter virus in terms of entry kinetics, cell-cell transmission and replicative capacity in primary cells. Our paired analysis revealed a higher sensitivity of several recipient virus isolates to interferon-α (IFNα) which suggests that resistance to IFNα cannot be a general driving force in T/F establishment. CONCLUSIONS: With the exception of increased IFNα sensitivity, none of the phenotypic virus properties we investigated clearly distinguished T/F viruses from their matched transmitter viruses supporting the notion that at least in subtype B infection HIV-1 transmission is to a considerable extent stochastic.


Asunto(s)
Infecciones por VIH/transmisión , VIH-1/genética , VIH-1/fisiología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Enfermedad Aguda , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Femenino , Variación Genética , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Homosexualidad Masculina , Humanos , Interferón-alfa/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/virología , Masculino , Pruebas de Neutralización , Fenotipo , Análisis de Secuencia de ADN , Procesos Estocásticos , Tropismo Viral , Internalización del Virus , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología
6.
Retrovirology ; 11: 75, 2014 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-25287422

RESUMEN

BACKGROUND: Variable loops 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 perform two key functions: ensuring envelope trimer entry competence and shielding against neutralizing antibodies. While preserving entry functionality would suggest a high need for V1V2 sequence optimization and conservation, shielding efficacy is known to depend on a high flexibility of V1V2 giving rise to its substantial sequence variability. How entry competence of the trimer is maintained despite the continuous emergence of antibody escape mutations within V1V2 has not been resolved. Since HIV cell-cell transmission is considered a highly effective means of virus dissemination, we investigated whether cell-cell transmission may serve to enhance infectivity of V1V2 variants with debilitated free virus entry. RESULTS: In a detailed comparison of wt and V1V2 mutant envelopes, V1V2 proved to be a key factor in ascertaining free virus infectivity, with V1V2 mutants displaying significantly reduced trimer integrity. Despite these defects, cell-cell transmission was able to partially rescue infectivity of V1V2 mutant viruses. We identified two regions, encompassing amino acids 156 to 160 (targeted by broadly neutralizing antibodies) and 175 to 180 (encompassing the α4ß7 binding site) which were particularly prone to free virus infectivity loss upon mutation but maintained infectivity in cell-cell transmission. Of note, V1V2 antibody shielding proved important during both free virus infection and cell-cell transmission. CONCLUSIONS: Based on our data we propose a model for V1V2 evolution that centers on cell-cell transmission as a salvage pathway for virus replication. Escape from antibody neutralization may frequently result in V1V2 mutations that reduce free virus infectivity. Cell-cell transmission could provide these escape viruses with sufficiently high replication levels that enable selection of compensatory mutations, thereby restoring free virus infectivity while ensuring antibody escape. Thus, our study highlights the need to factor in cell-cell transmission when considering neutralization escape pathways of HIV-1.


Asunto(s)
Proteína gp120 de Envoltorio del VIH/fisiología , VIH-1/patogenicidad , Evasión Inmune , Secuencia de Aminoácidos , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/química , Humanos , Mutación , Internalización del Virus
7.
J Virol ; 87(10): 5868-81, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23487463

RESUMEN

Here, we applied the designed ankyrin repeat protein (DARPin) technology to develop novel gp120-directed binding molecules with HIV entry-inhibiting capacity. DARPins are interesting molecules for HIV envelope inhibitor design, as their high-affinity binding differs from that of antibodies. DARPins in general prefer epitopes with a defined folded structure. We probed whether this capacity favors the selection of novel gp120-reactive molecules with specificities in epitope recognition and inhibitory activity that differ from those found among neutralizing antibodies. The preference of DARPins for defined structures was notable in our selections, since of the four gp120 modifications probed as selection targets, gp120 arrested by CD4 ligation proved the most successful. Of note, all the gp120-specific DARPin clones with HIV-neutralizing activity isolated recognized their target domains in a conformation-dependent manner. This was particularly pronounced for the V3 loop-specific DARPin 5m3_D12. In stark contrast to V3-specific antibodies, 5m3_D12 preferentially recognized the V3 loop in a specific conformation, as probed by structurally arrested V3 mimetic peptides, but bound linear V3 peptides only very weakly. Most notably, this conformation-dependent V3 recognition allowed 5m3_D12 to bypass the V1V2 shielding of several tier 2 HIV isolates and to neutralize these viruses. These data provide a proof of concept that the DARPin technology holds promise for the development of HIV entry inhibitors with a unique mechanism of action.


Asunto(s)
Repetición de Anquirina , Proteína gp120 de Envoltorio del VIH/metabolismo , Inhibidores de Fusión de VIH/metabolismo , Proteínas/metabolismo , Inhibidores de Fusión de VIH/aislamiento & purificación , Humanos , Unión Proteica , Conformación Proteica , Proteínas/aislamiento & purificación
8.
mBio ; 15(2): e0272223, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38270455

RESUMEN

Numerous clinical parameters link to severe coronavirus disease 2019, but factors that prevent symptomatic disease remain unknown. We investigated the impact of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and endemic human coronavirus (HCoV) antibody responses on symptoms in a longitudinal children cohort (n = 2,917) and a cross-sectional cohort including children and adults (n = 882), all first exposed to SARS-CoV-2 (March 2020 to March 2021) in Switzerland. Saliva (n = 4,993) and plasma (n = 7,486) antibody reactivity to the four HCoVs (subunit S1 [S1]) and SARS-CoV-2 (S1, receptor binding domain, subunit S2 [S2], nucleocapsid protein) was determined along with neutralizing activity against SARS-CoV-2 Wuhan, Alpha, Delta, and Omicron (BA.2) in a subset of individuals. Inferred recent SARS-CoV-2 infection was associated with a strong correlation between mucosal and systemic SARS-CoV-2 anti-spike responses. Individuals with pre-existing HCoV-S1 reactivity exhibited significantly higher antibody responses to SARS-CoV-2 in both plasma (IgG regression coefficients = 0.20, 95% CI = [0.09, 0.32], P < 0.001) and saliva (IgG regression coefficient = 0.60, 95% CI = [0.088, 1.11], P = 0.025). Saliva neutralization activity was modest but surprisingly broad, retaining activity against Wuhan (median NT50 = 32.0, 1Q-3Q = [16.4, 50.2]), Alpha (median NT50 = 34.9, 1Q-3Q = [26.0, 46.6]), and Delta (median NT50 = 28.0, 1Q-3Q = [19.9, 41.7]). In line with a rapid mucosal defense triggered by cross-reactive HCoV immunity, asymptomatic individuals presented with higher pre-existing HCoV-S1 activity in plasma (IgG HKU1, odds ratio [OR] = 0.53, 95% CI = [0.29,0.97], P = 0.038) and saliva (total HCoV, OR = 0.55, 95% CI = [0.33, 0.91], P = 0.019) and higher SARS-CoV-2 reactivity in saliva (IgG S2 fold change = 1.26, 95% CI = [1.03, 1.54], P = 0.030). By investigating the systemic and mucosal immune responses to SARS-CoV-2 and HCoVs in a population without prior exposure to SARS-CoV-2 or vaccination, we identified specific antibody reactivities associated with lack of symptom development.IMPORTANCEKnowledge of the interplay between human coronavirus (HCoV) immunity and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection is critical to understanding the coexistence of current endemic coronaviruses and to building knowledge potential future zoonotic coronavirus transmissions. This study, which retrospectively analyzed a large cohort of individuals first exposed to SARS-CoV-2 in Switzerland in 2020-2021, revealed several key findings. Pre-existing HCoV immunity, particularly mucosal antibody responses, played a significant role in improving SARS-CoV-2 immune response upon infection and reducing symptoms development. Mucosal neutralizing activity against SARS-CoV-2, although low in magnitude, retained activity against SARS-CoV-2 variants underlining the importance of maintaining local mucosal immunity to SARS-CoV-2. While the cross-protective effect of HCoV immunity was not sufficient to block infection by SARS-CoV-2, the present study revealed a remarkable impact on limiting symptomatic disease. These findings support the feasibility of generating pan-protective coronavirus vaccines by inducing potent mucosal immune responses.


Asunto(s)
COVID-19 , Adulto , Niño , Humanos , SARS-CoV-2 , Estudios Transversales , Estudios Retrospectivos , Inmunoglobulina G , Anticuerpos Antivirales , Glicoproteína de la Espiga del Coronavirus
9.
Blood ; 118(25): 6591-600, 2011 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-22021367

RESUMEN

In addition to adaptive T cells, the thymus supports the development of unconventional T cells such as natural killer T (NKT) and CD8αα intraepithelial lymphocytes (IELs), which have innate functional properties, particular antigenic specificities, and tissue localization. Both conventional and innate T cells are believed to develop from common precursors undergoing instructive, TCR-mediated lineage fate decisions, but innate T cells are proposed to undergo positive instead of negative selection in response to agonistic TCR signals. In the present study, we show that, in contrast to conventional αßT cells, innate αßT cells are not selected against functional TCRγ rearrangements and express TCRγ mRNA. Likewise, in contrast to the majority of γδT cells, thymic innate γδT cells are not efficiently selected against functional TCRß chains. In precursors of conventional T cells, autonomous TCR signals emanating from the pre-TCR or γδTCR in the absence of ligand mediate selection against the TCR of the opposite isotype and αß/γδ lineage commitment. Our data suggest that developing innate T cells ignore such signals and rely solely on agonistic TCR interactions. Consistently, most innate T cells reacted strongly against autologous thymocytes. These results suggest that innate and adaptive T-cell lineages do not develop from the same pool of precursors and potentially diverge before αß/γδ lineage commitment.


Asunto(s)
Linaje de la Célula/genética , Células Precursoras de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Inmunidad Adaptativa , Animales , Diversidad de Anticuerpos/genética , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Linaje de la Célula/inmunología , Femenino , Citometría de Flujo , Expresión Génica , Reordenamiento Génico de Linfocito T/genética , Inmunidad Innata , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Precursoras de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T/inmunología , Linfocitos T/metabolismo , Timocitos/inmunología , Timocitos/metabolismo
10.
Nat Struct Mol Biol ; 30(9): 1323-1336, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37605043

RESUMEN

The third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein trimer is indispensable for virus cell entry. Conformational masking of V3 within the trimer allows efficient neutralization via V3 only by rare, broadly neutralizing glycan-dependent antibodies targeting the closed prefusion trimer but not by abundant antibodies that access the V3 crown on open trimers after CD4 attachment. Here, we report on a distinct category of V3-specific inhibitors based on designed ankyrin repeat protein (DARPin) technology that reinstitute the CD4-bound state as a key neutralization target with up to >90% breadth. Broadly neutralizing DARPins (bnDs) bound V3 solely on open envelope and recognized a four-turn amphipathic α-helix in the carboxy-terminal half of V3 (amino acids 314-324), which we termed 'αV3C'. The bnD contact surface on αV3C was as conserved as the CD4 binding site. Molecular dynamics and escape mutation analyses underscored the functional relevance of αV3C, highlighting the potential of αV3C-based inhibitors and, more generally, of postattachment inhibition of HIV-1.


Asunto(s)
VIH-1 , Humanos , Aminoácidos , Anticuerpos , Sitios de Unión , Conformación Molecular
11.
J Exp Med ; 203(8): 2033-42, 2006 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-16880253

RESUMEN

The biological relevance of nonneutralizing antibodies elicited early after infection with noncytopathic persistence-prone viruses is unclear. We demonstrate that cytotoxic T lymphocyte-deficient TgH(KL25) mice, which are transgenic for the heavy chain of the lymphocytic choriomeningitis virus (LCMV)-neutralizing monoclonal antibody KL25, mount a focused neutralizing antibody response following LCMV infection, and that this results in the emergence of neutralization escape virus variants. Further investigation revealed that some of the escape variants that arose early after infection could still bind to the selecting antibody. In contrast, no antibody binding could be detected for late isolates, indicating that binding, but nonneutralizing, antibodies exerted a selective pressure on the virus. Infection of naive TgH(KL25) mice with distinct escape viruses differing in their antibody-binding properties revealed that nonneutralizing antibodies accelerated clearance of antibody-binding virus variants in a partly complement-dependent manner. Virus variants that did not bind antibodies were not affected. We therefore conclude that nonneutralizing antibodies binding to the same antigenic site as neutralizing antibodies are biologically relevant by limiting early viral spread.


Asunto(s)
Anticuerpos Antivirales/inmunología , Sitios de Unión de Anticuerpos/inmunología , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Glicoproteínas de Membrana/metabolismo , Proteínas Virales/inmunología , Animales , Antígenos Virales/química , Antígenos Virales/inmunología , Linfocitos B/inmunología , Activación de Complemento/inmunología , Glicoproteínas/química , Glicoproteínas/inmunología , Virus de la Coriomeningitis Linfocítica/química , Virus de la Coriomeningitis Linfocítica/genética , Ratones , Ratones Endogámicos C57BL , Pruebas de Neutralización , Proteínas Recombinantes/inmunología , Linfocitos T Citotóxicos/inmunología , Proteínas Virales/química
12.
J Clin Invest ; 132(12)2022 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-35482408

RESUMEN

BACKGROUNDNeutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The manner in which human infections respond to therapeutic SARS-CoV-2 antibodies, including convalescent plasma therapy, remains to be fully elucidated.METHODSWe conducted a proof-of-principle study of convalescent plasma therapy based on a phase I trial in 30 hospitalized COVID-19 patients with a median interval between onset of symptoms and first transfusion of 9 days (IQR, 7-11.8 days). Comprehensive longitudinal monitoring of the virological, serological, and disease status of recipients allowed deciphering of parameters on which plasma therapy efficacy depends.RESULTSIn this trial, convalescent plasma therapy was safe as evidenced by the absence of transfusion-related adverse events and low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (P = 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio, 3.0; 95% CI, 1.1-8.1; P = 0.026). The onset of endogenous neutralization affected viral clearance, but even after adjustment for their pretransfusion endogenous neutralization status, recipients benefitted from plasma therapy with high neutralizing antibodies (hazard ratio, 3.5; 95% CI, 1.1-11; P = 0.034).CONCLUSIONOur data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia before and after onset of the endogenous neutralizing response, and point beyond antibody-based interventions to critical laboratory parameters for improved evaluation of current and future SARS-CoV-2 therapies.TRIAL REGISTRATIONClinicalTrials.gov NCT04869072.FUNDINGThis study was funded via an Innovation Pool project by the University Hospital Zurich; the Swiss Red Cross Glückskette Corona Funding; Pandemiefonds of the UZH Foundation; and the Clinical Research Priority Program "Comprehensive Genomic Pathogen Detection" of the University of Zurich.


Asunto(s)
COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Formación de Anticuerpos , COVID-19/terapia , Vacunas contra la COVID-19 , Humanos , Inmunización Pasiva/efectos adversos , Prueba de Estudio Conceptual , Sueroterapia para COVID-19
13.
Nat Commun ; 12(1): 6703, 2021 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-34795285

RESUMEN

Determination of SARS-CoV-2 antibody responses in the context of pre-existing immunity to circulating human coronavirus (HCoV) is critical for understanding protective immunity. Here we perform a multifactorial analysis of SARS-CoV-2 and HCoV antibody responses in pre-pandemic (N = 825) and SARS-CoV-2-infected donors (N = 389) using a custom-designed multiplex ABCORA assay. ABCORA seroprofiling, when combined with computational modeling, enables accurate definition of SARS-CoV-2 seroconversion and prediction of neutralization activity, and reveals intriguing interrelations with HCoV immunity. Specifically, higher HCoV antibody levels in SARS-CoV-2-negative donors suggest that pre-existing HCoV immunity may provide protection against SARS-CoV-2 acquisition. In those infected, higher HCoV activity is associated with elevated SARS-CoV-2 responses, indicating cross-stimulation. Most importantly, HCoV immunity may impact disease severity, as patients with high HCoV reactivity are less likely to require hospitalization. Collectively, our results suggest that HCoV immunity may promote rapid development of SARS-CoV-2-specific immunity, thereby underscoring the importance of exploring cross-protective responses for comprehensive coronavirus prevention.


Asunto(s)
SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/metabolismo , COVID-19/inmunología , COVID-19/metabolismo , Coronavirus Humano 229E/inmunología , Coronavirus Humano 229E/metabolismo , Humanos , Inmunoglobulina G/metabolismo
14.
Wound Manag Prev ; 66(1): 24-29, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-32459658

RESUMEN

A rod passed through the mesenteric window is commonly used during maturation of ileostomies, but evidence for the effectiveness of this procedure is limited. PURPOSE: The aim of this meta-analysis was to determine whether ileostomy rods decrease stoma retraction rates in patients undergoing loop ileostomy (LI). METHODS: The PubMed, EMBASE, Cochrane Library, MEDLINE via Ovid, Cumulative Index of Nursing and Allied Health Literature, and Web of Science databases were systematically searched for randomized controlled trials (RCT) published in English from 1990 to the present date using the MeSH terms ostomy, rod, and bridge to compare ileostomies with a rod to those without a rod. Study information, patient demographics, characteristics, and stoma retraction rates were abstracted. The primary endpoint, stoma retraction, was defined as the disappearance of normal stomal protrusion to at, or below, skin level. The Mantel-Haenszel method of meta-analysis with odds ratio and 95% confidence interval (OR [95% CI]) was used. Among-study statistical heterogeneity was assessed using Cochrane chi-squared and I² tests. Tau² analysis to assess between-study variance was employed when I² was greater than 50%. The number needed to treat/harm (NNT) was calculated to assess clinical relevance of any statistical difference. Visual assessment of funnel plots and Egger's test were used to assess for publication bias. RESULTS: Of the 228 publications identified, 3 RCTs totaling 392 patients (194 LI with rod and 198 LI without rod) met the inclusion criteria for analysis. Overall bias risk was low. The stoma retraction rate was 3.1% (6/194) in patients with a rod versus 4.5% (9/198) in patients with LI without a rod at a mean follow-up of 3 months. This difference was not statistically or clinically significant (OR [95% CI] = 0.60 (0.21-1.72); P = .34; NNT = 69), with low statistical heterogeneity noted among the studies (I² = 0%). CONCLUSION: This meta-analysis found that ileostomy rods do not decrease stoma retraction rates at 3-month follow-up. Studies examining the rate of all potential complications in patients who do and do not receive rod placement following IL are needed to help surgeons make evidence-based decisions.


Asunto(s)
Ileostomía/efectos adversos , Ileostomía/instrumentación , Humanos , Ileostomía/métodos , Complicaciones Posoperatorias/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Resultado del Tratamiento
15.
J Exp Med ; 215(6): 1589-1608, 2018 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-29794117

RESUMEN

Understanding pathways that promote HIV-1 broadly neutralizing antibody (bnAb) induction is crucial to advance bnAb-based vaccines. We recently demarcated host, viral, and disease parameters associated with bnAb development in a large HIV-1 cohort screen. By establishing comprehensive antibody signatures based on IgG1, IgG2, and IgG3 activity to 13 HIV-1 antigens in 4,281 individuals in the same cohort, we now show that the same four parameters that are significantly linked with neutralization breadth, namely viral load, infection length, viral diversity, and ethnicity, also strongly influence HIV-1-binding antibody responses. However, the effects proved selective, shaping binding antibody responses in an antigen and IgG subclass-dependent manner. IgG response landscapes in bnAb inducers indicated a differentially regulated, IgG1-driven HIV-1 antigen response, and IgG1 binding of the BG505 SOSIP trimer proved the best predictor of HIV-1 neutralization breadth in plasma. Our findings emphasize the need to unravel immune modulators that underlie the differentially regulated IgG response in bnAb inducers to guide vaccine development.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Formación de Anticuerpos/inmunología , Anticuerpos Anti-VIH/inmunología , VIH-1/inmunología , Inmunoglobulina G/inmunología , Población Negra , Enfermedad Crónica , Demografía , Infecciones por VIH/inmunología , Humanos , Unión Proteica , Carga Viral , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología
16.
Nat Med ; 22(11): 1260-1267, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27668936

RESUMEN

Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen-viral load, length of untreated infection and viral diversity-independently drive bnAb evolution. Notably, black participants showed significantly (P = 0.0086-0.038) higher rates of bnAb induction than white participants. Neutralization fingerprint analysis, which was used to delineate plasma specificity, identified strong virus subtype dependencies, with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses (P = 0.02) and higher frequencies of V2-glycan-specific bnAbs in infection with non-subtype B viruses (P = 1 × 10-5). Thus, key host, disease and viral determinants, including subtype-specific envelope features that determine bnAb specificity, remain to be unraveled and harnessed for bnAb-based vaccine design.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Población Negra , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Carga Viral , Población Blanca , Vacunas contra el SIDA , Antígenos CD4/inmunología , Descubrimiento de Drogas , Femenino , Variación Genética , VIH-1/genética , Humanos , Modelos Lineales , Estudios Longitudinales , Masculino , Análisis Multivariante , Polisacáridos/inmunología , Estudios Prospectivos , ARN Viral/sangre , Suiza , Factores de Tiempo
17.
J Exp Med ; 208(7): 1419-33, 2011 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-21646396

RESUMEN

The HIV-1 envelope trimer adopts a quaternary conformation that effectively shields neutralization-sensitive domains and thus represents a major obstacle for natural and vaccine-elicited antibody responses. By using a structure-function analysis based on a specifically devised mathematical model, we demonstrate in this study that protection from neutralization is enforced by intersubunit contact between the variable loops 1 and 2 (V1V2) and domains of neighboring gp120 subunits in the trimer encompassing the V3 loop. Our data are consistent with an interaction of the V1V2 and V3 loop at the spike apex as proposed by cryoelectron tomography experiments. By defining the orientation of the V1V2 loop within the trimer toward the neighboring gp120 subunit's V3 loop, our data close an important gap in the understanding of the architecture of the trimeric spike. Knowledge on how the V1V2 barrier functions in the context of the trimer to mask conserved epitopes on gp120 may aid future vaccine design.


Asunto(s)
Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/metabolismo , VIH-1/química , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Secuencia de Aminoácidos , Anticuerpos Neutralizantes , Secuencia de Bases , Línea Celular , Reacciones Cruzadas , ADN Viral/genética , Epítopos/química , Anticuerpos Anti-VIH , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/inmunología , VIH-1/genética , VIH-1/inmunología , Humanos , Modelos Inmunológicos , Modelos Moleculares , Datos de Secuencia Molecular , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Dominios y Motivos de Interacción de Proteínas , Estructura Cuaternaria de Proteína
19.
Science ; 323(5912): 393-6, 2009 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-19150848

RESUMEN

Retroviruses have the potential to acquire host cell-derived genetic material during reverse transcription and can integrate into the genomes of larger, more complex DNA viruses. In contrast, RNA viruses were believed not to integrate into the host's genome under any circumstances. We found that illegitimate recombination between an exogenous nonretroviral RNA virus, lymphocytic choriomeningitis virus, and the endogenous intracisternal A-type particle (IAP) retrotransposon occurred and led to reverse transcription of exogenous viral RNA. The resulting complementary DNA was integrated into the host's genome with an IAP element. Thus, RNA viruses should be closely scrutinized for any capacity to interact with endogenous retroviral elements before their approval for therapeutic use in humans.


Asunto(s)
ADN Complementario/genética , Genes de Partícula A Intracisternal/genética , Virus de la Coriomeningitis Linfocítica/genética , ARN Viral/genética , Recombinación Genética , Transcripción Reversa , Integración Viral , Animales , Infecciones por Arenaviridae/virología , Secuencia de Bases , Línea Celular , Glicoproteínas/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Transfección , Proteínas Virales/genética
20.
Science ; 324(5934): 1576-80, 2009 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-19478140

RESUMEN

Chronic viral infection is often associated with the dysfunction of virus-specific T cells. Our studies using Il21r-deficient (Il21r-/-) mice now suggest that interleukin-21 (IL-21) is critical for the long-term maintenance and functionality of CD8+ T cells and the control of chronic lymphocytic choriomeningitis virus infection in mice. Cell-autonomous IL-21 receptor (IL-21R)-dependent signaling by CD8+ T cells was required for sustained cell proliferation and cytokine production during chronic infection. Il21r-/- mice showed normal CD8+ T cell expansion, effector function, memory homeostasis, and recall responses during acute and after resolved infection with several other nonpersistent viruses. These data suggest that IL-21R signaling is required for the maintenance of polyfunctional T cells during chronic viral infections and have implications for understanding the immune response to other persisting antigens, such as tumors.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Coriomeningitis Linfocítica/inmunología , Receptores de Interleucina-21/inmunología , Animales , Enfermedad Crónica , Humanos , Memoria Inmunológica , Interferón gamma/biosíntesis , Ratones , Ratones Endogámicos C57BL , Fragmentos de Péptidos/biosíntesis , Transducción de Señal
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA