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1.
Nat Immunol ; 22(10): 1294-1305, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34556879

RESUMEN

Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes include those encoding cytokines/chemokines associated with heightened protection from simian immunodeficiency virus challenge in NHPs. Expression of CREB1 target genes probably results from direct cGAMP (STING agonist)-modulated p-CREB1 activity that drives the recruitment of CD4+ T cells and B cells to the site of antigen presentation. Importantly, unlike NHPs immunized with ALVAC + Alum, those immunized with ALVAC + MF59, the regimen in the HVTN702 trial that showed no protection from HIV infection, exhibited significantly reduced CREB1 target gene expression. Our integrated systems biology approach has validated CREB1 as a critical driver of vaccine efficacy and highlights that adjuvants that trigger CREB1 signaling may be critical for efficacious HIV-1 vaccines.


Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Inmunogenicidad Vacunal/inmunología , Vacunas Virales/inmunología , Vacunas contra el SIDA/inmunología , Adyuvantes Inmunológicos/farmacología , Animales , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Expresión Génica/inmunología , Vectores Genéticos/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/virología , Humanos , Inmunización/métodos , Primates/inmunología , Primates/virología , Vacunación/métodos
2.
Nat Immunol ; 22(12): 1503-1514, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34716452

RESUMEN

Prevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/metabolismo , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/metabolismo , Sitios de Unión/genética , COVID-19/metabolismo , COVID-19/prevención & control , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Mapeo Epitopo , Epítopos/química , Epítopos/inmunología , Epítopos/metabolismo , Humanos , Ratones Transgénicos , Pruebas de Neutralización , Unión Proteica , Conformación Proteica , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Homología de Secuencia de Aminoácido , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Análisis de Supervivencia
3.
Nat Immunol ; 20(7): 824-834, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31209403

RESUMEN

Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4+ T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3' untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4+ T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression.


Asunto(s)
Regulación de la Expresión Génica , Variación Genética , Infecciones por VIH/genética , Infecciones por VIH/virología , VIH-1 , ARN sin Sentido/genética , ARN Largo no Codificante/genética , Receptores CCR5/genética , Regiones no Traducidas 3' , Alelos , Biomarcadores , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Membrana Celular/metabolismo , Genes Reporteros , Genotipo , Infecciones por VIH/metabolismo , Humanos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Grupos de Población/genética , Pronóstico , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores CCR5/metabolismo , Carga Viral
5.
Cell ; 163(4): 988-98, 2015 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-26544943

RESUMEN

While antibody titers and neutralization are considered the gold standard for the selection of successful vaccines, these parameters are often inadequate predictors of protective immunity. As antibodies mediate an array of extra-neutralizing Fc functions, when neutralization fails to predict protection, investigating Fc-mediated activity may help identify immunological correlates and mechanism(s) of humoral protection. Here, we used an integrative approach termed Systems Serology to analyze relationships among humoral responses elicited in four HIV vaccine trials. Each vaccine regimen induced a unique humoral "Fc fingerprint." Moreover, analysis of case:control data from the first moderately protective HIV vaccine trial, RV144, pointed to mechanistic insights into immune complex composition that may underlie protective immunity to HIV. Thus, multi-dimensional relational comparisons of vaccine humoral fingerprints offer a unique approach for the evaluation and design of novel vaccines against pathogens for which correlates of protection remain elusive.


Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Antivirales/inmunología , Inmunoglobulina G/inmunología , Animales , Anticuerpos Antivirales/sangre , Citotoxicidad Celular Dependiente de Anticuerpos , Complejo Antígeno-Anticuerpo/inmunología , Ensayos Clínicos como Asunto , Diseño de Fármacos , Infecciones por VIH/inmunología , Humanos , Inmunoglobulina G/sangre , Receptores Fc/inmunología
6.
Cell ; 159(5): 969-972, 2014 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-25416935

RESUMEN

Despite major advances in HIV-1 therapeutics and prevention strategies, the development of a safe and effective prophylactic HIV-1 vaccine will likely be critical for ending the global HIV-1 epidemic. Yet only four HIV-1 vaccine concepts have been tested for clinical efficacy over the past 30 years. In this Commentary, we describe key hurdles facing the HIV-1 vaccine development field and outline strategies to accelerate efficacy evaluation of novel HIV-1 vaccine candidates.


Asunto(s)
Vacunas contra el SIDA/uso terapéutico , Ensayos Clínicos como Asunto , VIH-1/fisiología , Investigación Biomédica/economía , Ensayos Clínicos como Asunto/economía , Femenino , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , VIH-1/genética , Humanos , Masculino
7.
Cell ; 155(3): 531-9, 2013 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-24243013

RESUMEN

The global diversity of HIV-1 represents a critical challenge facing HIV-1 vaccine development. HIV-1 mosaic antigens are bioinformatically optimized immunogens designed for improved coverage of HIV-1 diversity. However, the protective efficacy of such global HIV-1 vaccine antigens has not previously been evaluated. Here, we demonstrate the capacity of bivalent HIV-1 mosaic antigens to protect rhesus monkeys against acquisition of infection following heterologous challenges with the difficult-to-neutralize simian-human immunodeficiency virus SHIV-SF162P3. Adenovirus/poxvirus and adenovirus/adenovirus vector-based vaccines expressing HIV-1 mosaic Env, Gag, and Pol afforded a significant reduction in the per-exposure acquisition risk following repetitive, intrarectal SHIV-SF162P3 challenges. Protection against acquisition of infection correlated with vaccine-elicited binding, neutralizing, and functional nonneutralizing antibodies, suggesting that the coordinated activity of multiple antibody functions may contribute to protection against difficult-to-neutralize viruses. These data demonstrate the protective efficacy of HIV-1 mosaic antigens and suggest a potential strategy for the development of a global HIV-1 vaccine. PAPERCLIP:


Asunto(s)
Vacunas contra el SIDA/inmunología , VIH-1 , Animales , Formación de Anticuerpos , Femenino , Antígenos VIH/inmunología , Proteínas del Virus de la Inmunodeficiencia Humana/inmunología , Inmunidad Celular , Macaca mulatta , Masculino , Datos de Secuencia Molecular , Organismos Libres de Patógenos Específicos
8.
Immunity ; 46(2): 176-182, 2017 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-28228277

RESUMEN

A recent unprecedented outbreak of Zika virus (ZIKV) in the Americas has been associated with microcephaly and other congenital malformations in infants as well as Guillain-Barre syndrome in adults. The development of a safe and effective ZIKV vaccine is therefore an urgent global health priority. Promising data from preclinical vaccine studies in mice and monkeys suggest that an effective vaccine will likely be possible, but important scientific challenges remain. Here we review the current state of ZIKV vaccine development. We discuss different vaccination strategies and we highlight challenges facing clinical evaluation of ZIKV vaccine candidates.


Asunto(s)
Vacunas Virales , Infección por el Virus Zika/prevención & control , Virus Zika , Animales , Humanos
9.
J Virol ; 98(8): e0028124, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39046263

RESUMEN

HLA class I variation has the strongest effect genome-wide on outcome after HIV infection, and as such, an understanding of the impact of HLA polymorphism on response to HIV vaccination may inform vaccine design. We sought HLA associations with HIV-directed immunogenicity in the phase 1/2a APPROACH vaccine trial, which tested vaccine regimens containing mosaic inserts in Ad26 and MVA vectors, with or without a trimeric gp140 protein. While there were no HLA allelic associations with the overall cellular immune response to the vaccine assessed by ELISpot (Gag, Pol, and Env combined), significant associations with differential response to Gag compared to Env antigens were observed. Notably, HLA class I alleles known to associate with disease susceptibility in HIV natural history cohorts are associated with stronger Env-directed responses, whereas protective alleles are associated with stronger Gag-directed responses. Mean viral loads determined for each HLA allele in untreated individuals correlated negatively with the strength of the Gag response minus the Env response in Black vaccinees based on both ELISpot and CD8+ T cell ICS responses. As the association of T cell responses to conserved Gag epitopes with lower viral load in untreated individuals is well established, our data raise the possibility that the Ad26.Mos.HIV vaccine may induce more effective cellular responses in those with HLA alleles that confer improved virologic control in untreated HIV infection.IMPORTANCENo vaccine tested to date has shown sufficient efficacy against HIV infection. A vaccine that induces robust responses in one individual may fail to do so in another individual due to variation in HLA class I genes, loci central to the immune response. Extensive data have shown the strong effect of HLA variation on outcome after HIV infection, but very little is known about the effect of such variation on HIV vaccine success. Here, we identify a link between the effect of HLA variation on HIV disease outcome and immune responses to an HIV vaccine. HLA variants associated with better HIV control after infection also induce stronger responses against the HIV Gag protein relative to the Env protein after vaccination. Given the virologic control conferred by responses to Gag in natural history of HIV infection, these data suggest that HLA alleles conferring protection after HIV infection may also support a more effective cellular response to HIV vaccination.


Asunto(s)
Vacunas contra el SIDA , Alelos , Infecciones por VIH , VIH-1 , Productos del Gen env del Virus de la Inmunodeficiencia Humana , Productos del Gen gag del Virus de la Inmunodeficiencia Humana , Humanos , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/administración & dosificación , VIH-1/inmunología , VIH-1/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/genética , Infecciones por VIH/prevención & control , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Masculino , Carga Viral , Adulto , Femenino , Linfocitos T CD8-positivos/inmunología
10.
PLoS Pathog ; 19(5): e1011359, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37256916

RESUMEN

The modestly efficacious HIV-1 vaccine regimen (RV144) conferred 31% vaccine efficacy at 3 years following the four-shot immunization series, coupled with rapid waning of putative immune correlates of decreased infection risk. New strategies to increase magnitude and durability of protective immunity are critically needed. The RV305 HIV-1 clinical trial evaluated the immunological impact of a follow-up boost of HIV-1-uninfected RV144 recipients after 6-8 years with RV144 immunogens (ALVAC-HIV alone, AIDSVAX B/E gp120 alone, or ALVAC-HIV + AIDSVAX B/E gp120). Previous reports demonstrated that this regimen elicited higher binding, antibody Fc function, and cellular responses than the primary RV144 regimen. However, the impact of the canarypox viral vector in driving antibody specificity, breadth, durability and function is unknown. We performed a follow-up analysis of humoral responses elicited in RV305 to determine the impact of the different booster immunogens on HIV-1 epitope specificity, antibody subclass, isotype, and Fc effector functions. Importantly, we observed that the ALVAC vaccine component directly contributed to improved breadth, function, and durability of vaccine-elicited antibody responses. Extended boosts in RV305 increased circulating antibody concentration and coverage of heterologous HIV-1 strains by V1V2-specific antibodies above estimated protective levels observed in RV144. Antibody Fc effector functions, specifically antibody-dependent cellular cytotoxicity and phagocytosis, were boosted to higher levels than was achieved in RV144. V1V2 Env IgG3, a correlate of lower HIV-1 risk, was not increased; plasma Env IgA (specifically IgA1), a correlate of increased HIV-1 risk, was elevated. The quality of the circulating polyclonal antibody response changed with each booster immunization. Remarkably, the ALVAC-HIV booster immunogen induced antibody responses post-second boost, indicating that the viral vector immunogen can be utilized to selectively enhance immune correlates of decreased HIV-1 risk. These results reveal a complex dynamic of HIV-1 immunity post-vaccination that may require careful balancing to achieve protective immunity in the vaccinated population. Trial registration: RV305 clinical trial (ClinicalTrials.gov number, NCT01435135). ClinicalTrials.gov Identifier: NCT00223080.


Asunto(s)
Vacunas contra el SIDA , Infecciones por VIH , Seropositividad para VIH , VIH-1 , Humanos , Formación de Anticuerpos , Infecciones por VIH/prevención & control , Inmunización Secundaria/métodos , Especificidad de Anticuerpos , Anticuerpos Anti-VIH , Proteína gp120 de Envoltorio del VIH
11.
Immunity ; 44(1): 167-178, 2016 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-26795249

RESUMEN

A central effort in HIV vaccine development is to generate protective broadly neutralizing antibodies, a process dependent on T follicular helper (Tfh) cells. The feasibility of using peripheral blood counterparts of lymph node Tfh cells to assess the immune response and the influence of viral and vaccine antigens on their helper functions remain obscure. We assessed circulating HIV-specific IL-21(+)CD4(+) T cells and showed transcriptional and phenotypic similarities to lymphoid Tfh cells, and hence representing peripheral Tfh (pTfh) cells. pTfh cells were functionally active and B cell helper quality differed depending on antigen specificity. Furthermore, we found higher frequency of pTfh cells in peripheral blood mononuclear cell specimens from the ALVAC+AIDSVAX (RV144) HIV vaccine trial associated with protective antibody responses compared to the non-protective DNA+Ad5 vaccine trial. Together, we identify IL-21(+)CD4(+) T cells as pTfh cells, implicating them as key populations in the generation of vaccine-evoked antibody responses.


Asunto(s)
Infecciones por VIH/inmunología , Interleucinas/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Separación Celular , Ensayo de Immunospot Ligado a Enzimas , Citometría de Flujo , VIH-1/inmunología , Humanos , Reacción en Cadena en Tiempo Real de la Polimerasa
12.
J Virol ; 97(2): e0163522, 2023 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-36749076

RESUMEN

Understanding the dynamics of early immune responses to HIV-1 infection, including the evolution of initial neutralizing and antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies, will inform HIV vaccine design. In this study, we assess the development of autologous neutralizing antibodies (ANAbs) against founder envelopes (Envs) from 18 participants with HIV-1 CRF01_AE acute infection. The timing of ANAb development directly associated with the magnitude of the longitudinal ANAb response. Participants that developed ANAbs within 6 months of infection had significantly higher ANAb responses at 1 year (50% inhibitory concentration [IC50] geometric mean titer [GMT] = 2,010 versus 184; P = 0.001) and 2 years (GMT = 3,479 versus 340; P = 0.015), compared to participants that developed ANAb responses after 6 months. Participants with later development of ANAb tended to develop an earlier, potent heterologous tier 1 (92TH023) neutralizing antibody (NAb) response (P = 0.049). CRF01_AE founder Env V1V2 loop lengths correlated indirectly with the timing (P = 0.002, r = -0.675) and directly with magnitude (P = 0.005, r = 0.635) of ANAb responses; Envs with longer V1V2 loop lengths elicited earlier and more potent ANAb responses. While ANAb responses did not associate with viral load, the viral load set point correlated directly with neutralization of the heterologous 92TH023 strain (P = 0.007, r = 0.638). In contrast, a striking inverse correlation was observed between viral load set point and peak ADCC against heterologous 92TH023 Env strain (P = 0.0005, r = -0.738). These data indicate that specific antibody functions can be differentially related to viral load set point and may affect HIV-1 pathogenesis. Exploiting Env properties, such as V1V2 length, could facilitate development of subtype-specific vaccines that elicit more effective immune responses and improved protection. IMPORTANCE Development of an effective HIV-1 vaccine will be facilitated by better understanding the dynamics between the founder virus and the early humoral responses. Variations between subtypes may influence the evolution of immune responses and should be considered as we strive to understand these dynamics. In this study, autologous founder envelope neutralization and heterologous functional humoral responses were evaluated after acute infection by HIV-1 CRF01_AE, a subtype that has not been thoroughly characterized. The evolution of these humoral responses was assessed in relation to envelope characteristics, magnitude of elicited immune responses, and viral load. Understanding immune parameters in natural infection will improve our understanding of protective responses and aid in the development of immunogens that elicit protective functional antibodies. Advancing our knowledge of correlates of positive clinical outcomes should lead to the design of more efficacious vaccines.


Asunto(s)
Anticuerpos Neutralizantes , Formación de Anticuerpos , Anticuerpos Anti-VIH , Infecciones por VIH , Productos del Gen env del Virus de la Inmunodeficiencia Humana , Humanos , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Infecciones por VIH/inmunología , VIH-1
13.
J Virol ; 97(7): e0159622, 2023 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-37395646

RESUMEN

Novel therapeutic monoclonal antibodies (MAbs) must accommodate comprehensive breadth of activity against diverse sarbecoviruses and high neutralization potency to overcome emerging variants. Here, we report the crystal structure of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD) in complex with MAb WRAIR-2063, a moderate-potency neutralizing antibody with exceptional sarbecovirus breadth, that targets the highly conserved cryptic class V epitope. This epitope overlaps substantially with the spike protein N-terminal domain (NTD) -interacting region and is exposed only when the spike is in the open conformation, with one or more RBDs accessible. WRAIR-2063 binds the RBD of SARS-CoV-2 WA-1, all variants of concern (VoCs), and clade 1 to 4 sarbecoviruses with high affinity, demonstrating the conservation of this epitope and potential resiliency against variation. We compare structural features of additional class V antibodies with their reported neutralization capacity to further explore the utility of the class V epitope as a pan-sarbecovirus vaccine and therapeutic target. IMPORTANCE Characterization of MAbs against SARS-CoV-2, elicited through vaccination or natural infection, has provided vital immunotherapeutic options for curbing the COVID-19 pandemic and has supplied critical insights into SARS-CoV-2 escape, transmissibility, and mechanisms of viral inactivation. Neutralizing MAbs that target the RBD but do not block ACE2 binding are of particular interest because the epitopes are well conserved within sarbecoviruses and MAbs targeting this area demonstrate cross-reactivity. The class V RBD-targeted MAbs localize to an invariant site of vulnerability, provide a range of neutralization potency, and exhibit considerable breadth against divergent sarbecoviruses, with implications for vaccine and therapeutic development.


Asunto(s)
Anticuerpos Antivirales , COVID-19 , Epítopos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Humanos , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/metabolismo , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/química , Anticuerpos Antivirales/metabolismo , Epítopos/química , SARS-CoV-2/química , SARS-CoV-2/metabolismo , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/química , Dominios Proteicos , Cristalografía por Rayos X , Estructura Cuaternaria de Proteína , Modelos Moleculares , Línea Celular
14.
PLoS Pathog ; 18(3): e1010369, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35303045

RESUMEN

Eliciting broadly neutralizing antibodies (bnAbs) is a cornerstone of HIV-1 vaccine strategies. Comparing HIV-1 envelope (env) sequences from the first weeks of infection to the breadth of antibody responses observed several years after infection can help define viral features critical to vaccine design. We investigated the relationship between HIV-1 env genetics and the development of neutralization breadth in 70 individuals enrolled in a prospective acute HIV-1 cohort. Half of the individuals who developed bnAbs were infected with multiple HIV-1 founder variants, whereas all individuals with limited neutralization breadth had been infected with single HIV-1 founders. Accordingly, at HIV-1 diagnosis, env diversity was significantly higher in participants who later developed bnAbs compared to those with limited breadth (p = 0.012). This association between founder multiplicity and the subsequent development of neutralization breadth was also observed in 56 placebo recipients in the RV144 vaccine efficacy trial. In addition, we found no evidence that neutralization breath was heritable when analyzing env sequences from the 126 participants. These results demonstrate that the presence of slightly different HIV-1 variants in acute infection could promote the induction of bnAbs, suggesting a novel vaccine strategy, whereby an initial immunization with a cocktail of minimally distant antigens would be able to initiate bnAb development towards breadth.


Asunto(s)
VIH-1 , Anticuerpos Neutralizantes , Epítopos , Anticuerpos Anti-VIH , VIH-1/genética , Humanos , Estudios Prospectivos , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética
15.
Virol J ; 21(1): 148, 2024 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-38951814

RESUMEN

The magnitude of the HIV-1 epidemic in Nigeria is second only to the subtype C epidemic in South Africa, yet the subtypes prevalent in Nigeria require further characterization. A panel of 50 subtype G and 18 CRF02_AG Nigerian HIV-1 pseudoviruses (PSV) was developed and envelope coreceptor usage, neutralization sensitivity and cross-clade reactivity were characterized. These PSV were neutralized by some antibodies targeting major neutralizing determinants, but potentially important differences were observed in specific sensitivities (eg. to sCD4, MPER and V2/V3 monoclonal antibodies), as well as in properties such as variable loop lengths, number of potential N-linked glycans and charge, demonstrating distinct antigenic characteristics of CRF02_AG and subtype G. There was preferential neutralization of the matched CRF/subtype when PSV from subtype G or CRF02_AG were tested using pooled plasma. These novel Nigerian PSV will be useful to study HIV-1 CRF- or subtype-specific humoral immune responses for subtype G and CRF02_AG.


Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , Infecciones por VIH , VIH-1 , Pruebas de Neutralización , VIH-1/inmunología , VIH-1/genética , VIH-1/clasificación , Nigeria , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Humanos , Anticuerpos Anti-VIH/inmunología , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Reacciones Cruzadas/inmunología
16.
BMC Public Health ; 24(1): 2692, 2024 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-39358725

RESUMEN

INTRODUCTION: Sub-Saharan Africa has a high burden of HIV, particularly among female sex workers (FSW) and men who have sex with men (MSM). Future clinical trials to evaluate vaccines and other interventions to prevent HIV will need to enroll populations with high HIV incidence. We conducted an observational study of HIV incidence among men and women with multiple sexual partners-including MSM and FSW-in Maputo, Mozambique, in order to prepare the country to conduct future efficacy trials of candidate HIV vaccines and other HIV prevention products. METHODS: We conducted a prospective observational HIV incidence study in Maputo, Mozambique, that enrolled adults aged 18-35 years, without HIV, who had two or more sexual partners in the preceding three months. Recruitment strategies prioritized participation of MSM and FSW. Participants were followed for 24 months with HIV-1 testing every 3 months and staff-administered behavioral questionnaires every 6 months. Cox proportional hazard modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for factors potentially associated with HIV acquisition. RESULTS: From January 2014 to October 2017, 505 adults without HIV were enrolled with median age of 21 years (interquartile range:19-24); 41% were female and 82% were single. There were 19 HIV seroconversions (10 female and 9 male) during 943 person-years (PY) of observation (overall HIV incidence 2.02/100PY; 95%CI 1.21-3.15). The highest HIV incidence was observed among sex workers (2.08/100PY; 95%CI 0.25-7.52) and MSM (19.18/100PY; 95%CI 3.96-56.06). Increased hazard of incident HIV was observed among participants who were MSM (HR = 27.95, 95%CI 4.39-117.94), p = 0.0004), reported three or more sexual partners at enrollment (HR = 7.39, 95%CI 1.64-33.25, p = 0.009), and indicated ever having a sexual partner living with HIV (HR = 9.64, 95%CI 2.23-41.71, p = 0.002). CONCLUSION: Our findings may inform inclusion criteria for upcoming clinical trials of HIV prevention interventions, including vaccine candidates, which may prioritize enrollment of MSM, people with more than three sexual partners, and people with sexual partners who are living with HIV. These same populations are in need of further intervention to reduce HIV incidence.


Asunto(s)
Infecciones por VIH , Trabajadores Sexuales , Parejas Sexuales , Humanos , Masculino , Mozambique/epidemiología , Femenino , Incidencia , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Adulto , Adulto Joven , Estudios Prospectivos , Adolescente , Trabajadores Sexuales/estadística & datos numéricos , Trabajadores Sexuales/psicología , Homosexualidad Masculina/estadística & datos numéricos , Homosexualidad Masculina/psicología , Vacunas contra el SIDA , Factores de Riesgo , Conducta Sexual/estadística & datos numéricos
17.
Proc Natl Acad Sci U S A ; 118(46)2021 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-34753817

RESUMEN

Acute HIV-1 infection (AHI) results in the widespread depletion of CD4+ T cells in peripheral blood and gut mucosal tissue. However, the impact on the predominantly CD4+ immunoregulatory invariant natural killer T (iNKT) cells during AHI remains unknown. Here, iNKT cells from peripheral blood and colonic mucosa were investigated during treated and untreated AHI. iNKT cells in blood were activated and rapidly depleted in untreated AHI. At the time of peak HIV-1 viral load, these cells showed the elevated expression of cell death-associated transcripts compared to preinfection. Residual peripheral iNKT cells suffered a diminished responsiveness to in vitro stimulation early into chronic infection. Additionally, HIV-1 DNA, as well as spliced and unspliced viral RNA, were detected in iNKT cells isolated from blood, indicating the active infection of these cells in vivo. The loss of iNKT cells occurred from Fiebig stage III in the colonic mucosa, and these cells were not restored to normal levels after initiation of ART during AHI. CD4+ iNKT cells were depleted faster and more profoundly than conventional CD4+ T cells, and the preferential infection of CD4+ iNKT cells over conventional CD4+ T cells was confirmed by in vitro infection experiments. In vitro data also provided evidence of latent infection in iNKT cells. Strikingly, preinfection levels of peripheral blood CD4+ iNKT cells correlated directly with the peak HIV-1 load. These findings support a model in which iNKT cells are early targets for HIV-1 infection, driving their rapid loss from circulation and colonic mucosa.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Colon/inmunología , Colon/virología , Infecciones por VIH/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/virología , Células T Asesinas Naturales/inmunología , Adolescente , Adulto , Progresión de la Enfermedad , Femenino , Infecciones por VIH/virología , VIH-1/inmunología , Humanos , Masculino , Persona de Mediana Edad , Infección Persistente/inmunología , Infección Persistente/virología , Adulto Joven
18.
J Virol ; 96(2): e0159921, 2022 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-34705557

RESUMEN

Live oral vaccines have been explored for their protective efficacy against respiratory viruses, particularly for adenovirus serotypes 4 and 7. The potential of a live oral vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, remains unclear. In this study, we assessed the immunogenicity of live SARS-CoV-2 delivered to the gastrointestinal tract in rhesus macaques and its protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge. Postpyloric administration of SARS-CoV-2 by esophagogastroduodenoscopy resulted in limited virus replication in the gastrointestinal tract and minimal to no induction of mucosal antibody titers in rectal swabs, nasal swabs, and bronchoalveolar lavage fluid. Low levels of serum neutralizing antibodies were induced and correlated with modestly diminished viral loads in nasal swabs and bronchoalveolar lavage fluid following intranasal and intratracheal SARS-CoV-2 challenge. Overall, our data show that postpyloric inoculation of live SARS-CoV-2 is weakly immunogenic and confers partial protection against respiratory SARS-CoV-2 challenge in rhesus macaques. IMPORTANCE SARS-CoV-2 remains a global threat, despite the rapid deployment but limited coverage of multiple vaccines. Alternative vaccine strategies that have favorable manufacturing timelines, greater ease of distribution, and improved coverage may offer significant public health benefits, especially in resource-limited settings. Live oral vaccines have the potential to address some of these limitations; however, no studies have yet been conducted to assess the immunogenicity and protective efficacy of a live oral vaccine against SARS-CoV-2. Here, we report that oral administration of live SARS-CoV-2 in nonhuman primates may offer prophylactic benefits, but the formulation and route of administration will require further optimization.


Asunto(s)
Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , Administración Oral , Animales , Femenino , Macaca mulatta , Masculino , Eficacia de las Vacunas
19.
PLoS Pathog ; 17(6): e1009673, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34170962

RESUMEN

Pre-existing immunity to flaviviruses can influence the outcome of subsequent flavivirus infections. Therefore, it is critical to determine whether baseline DENV immunity may influence subsequent ZIKV infection and the protective efficacy of ZIKV vaccines. In this study, we investigated the impact of pre-existing DENV immunity induced by vaccination on ZIKV infection and the protective efficacy of an inactivated ZIKV vaccine. Rhesus macaques and mice inoculated with a live attenuated DENV vaccine developed neutralizing antibodies (NAbs) to multiple DENV serotypes but no cross-reactive NAbs responses to ZIKV. Animals with baseline DENV NAbs did not exhibit enhanced ZIKV infection and showed no overall reduction in ZIKV vaccine protection. Moreover, passive transfer of purified DENV-specific IgG from convalescent human donors did not augment ZIKV infection in STAT2 -/- and BALB/c mice. In summary, these results suggest that baseline DENV immunity induced by vaccination does not significantly enhance ZIKV infection or impair the protective efficacy of candidate ZIKV vaccines in these models. These data can help inform immunization strategies in regions of the world with multiple circulating pathogenic flaviviruses.


Asunto(s)
Anticuerpos Antivirales/inmunología , Vacunas contra el Dengue/inmunología , Infección por el Virus Zika/prevención & control , Animales , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Reacciones Cruzadas/inmunología , Humanos , Macaca mulatta , Ratones , Vacunas Virales/inmunología
20.
PLoS Pathog ; 17(2): e1009339, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33600506

RESUMEN

Toll-like receptor 7 (TLR7) agonist and PGT121 (broadly neutralizing antibody, bnAb) administration previously delayed viral rebound and induced SHIV remission. We evaluated the impact of GS-986 (TLR7 agonist) and dual bnAbs on viral rebound after antiretroviral therapy (ART) interruption. Rhesus macaques inoculated with SHIV-1157ipd3N4 were initiated on daily suppressive ART from Day 14 post SHIV inoculation. Active arm animals (n = 8) received GS-986, N6-LS and PGT121 after plasma viral suppression, starting from week 14. GS-986 induced immune activation and SHIV-specific T cell responses but not viral expression in all the active arm animals. After ART interruption, median time to viral rebound was 6 weeks in the active and 3 weeks in the control arm (p = 0.024). In this animal model, the administration of the combination of GS-986 and dual bnAbs was associated with a modest delay in viral rebound. This strategy should be further evaluated to better understand the underlying mechanisms for the induction of virus-specific immune responses and delay in viral rebound.


Asunto(s)
Antirretrovirales/farmacología , Anticuerpos Neutralizantes/farmacología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/efectos de los fármacos , Receptor Toll-Like 7/agonistas , Carga Viral , Viremia/inmunología , Animales , Macaca mulatta , Masculino , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Viremia/tratamiento farmacológico , Viremia/virología
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