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1.
Annu Rev Immunol ; 38: 673-703, 2020 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-32340576

RESUMEN

Development of improved approaches for HIV-1 prevention will likely be required for a durable end to the global AIDS pandemic. Recent advances in preclinical studies and early phase clinical trials offer renewed promise for immunologic strategies for blocking acquisition of HIV-1 infection. Clinical trials are currently underway to evaluate the efficacy of two vaccine candidates and a broadly neutralizing antibody (bNAb) to prevent HIV-1 infection in humans. However, the vast diversity of HIV-1 is a major challenge for both active and passive immunization. Here we review current immunologic strategies for HIV-1 prevention, with a focus on current and next-generation vaccines and bNAbs.


Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Interacciones Huésped-Patógeno/inmunología , Vacunas contra el SIDA/administración & dosificación , Animales , Ensayos Clínicos como Asunto , Manejo de la Enfermedad , Variación Genética , Infecciones por VIH/virología , VIH-1/genética , Humanos , Inmunización Pasiva , ARN Viral , Relación Estructura-Actividad , Linfocitos T/inmunología , Linfocitos T/metabolismo , Proteínas Virales/química , Proteínas Virales/genética
2.
Annu Rev Immunol ; 36: 603-638, 2018 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-29490165

RESUMEN

Globally, about 36.7 million people were living with HIV infection at the end of 2015. The most frequent infection co-occurring with HIV-1 is Mycobacterium tuberculosis-374,000 deaths per annum are attributable to HIV-tuberculosis, 75% of those occurring in Africa. HIV-1 infection increases the risk of tuberculosis by a factor of up to 26 and alters its clinical presentation, complicates diagnosis and treatment, and worsens outcome. Although HIV-1-induced depletion of CD4+ T cells underlies all these effects, more widespread immune deficits also contribute to susceptibility and pathogenesis. These defects present a challenge to understand and ameliorate, but also an opportunity to learn and optimize mechanisms that normally protect people against tuberculosis. The most effective means to prevent and ameliorate tuberculosis in HIV-1-infected people is antiretroviral therapy, but this may be complicated by pathological immune deterioration that in turn requires more effective host-directed anti-inflammatory therapies to be derived.


Asunto(s)
Coinfección , Infecciones por VIH/inmunología , VIH-1/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Animales , Terapia Antirretroviral Altamente Activa , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Progresión de la Enfermedad , Variación Genética , Infecciones por VIH/diagnóstico , Infecciones por VIH/terapia , Infecciones por VIH/virología , VIH-1/genética , Humanos , Tuberculosis/diagnóstico , Tuberculosis/microbiología , Tuberculosis/terapia , Replicación Viral
3.
Cell ; 187(12): 2919-2934.e20, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38761800

RESUMEN

A critical roadblock to HIV vaccine development is the inability to induce B cell lineages of broadly neutralizing antibodies (bnAbs) in humans. In people living with HIV-1, bnAbs take years to develop. The HVTN 133 clinical trial studied a peptide/liposome immunogen targeting B cell lineages of HIV-1 envelope (Env) membrane-proximal external region (MPER) bnAbs (NCT03934541). Here, we report MPER peptide-liposome induction of polyclonal HIV-1 B cell lineages of mature bnAbs and their precursors, the most potent of which neutralized 15% of global tier 2 HIV-1 strains and 35% of clade B strains with lineage initiation after the second immunization. Neutralization was enhanced by vaccine selection of improbable mutations that increased antibody binding to gp41 and lipids. This study demonstrates proof of concept for rapid vaccine induction of human B cell lineages with heterologous neutralizing activity and selection of antibody improbable mutations and outlines a path for successful HIV-1 vaccine development.


Asunto(s)
Vacunas contra el SIDA , Anticuerpos Neutralizantes , Linfocitos B , Anticuerpos Anti-VIH , VIH-1 , Humanos , Vacunas contra el SIDA/inmunología , VIH-1/inmunología , Anticuerpos Neutralizantes/inmunología , Linfocitos B/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Linaje de la Célula , Liposomas , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Mutación , Proteína gp41 de Envoltorio del VIH/inmunología
4.
Annu Rev Immunol ; 34: 635-59, 2016 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-27168247

RESUMEN

HIV employs multiple means to evade the humoral immune response, particularly the elicitation of and recognition by broadly neutralizing antibodies (bnAbs). Such antibodies can act antivirally against a wide spectrum of viruses by targeting relatively conserved regions on the surface HIV envelope trimer spike. Elicitation of and recognition by bnAbs are hindered by the arrangement of spikes on virions and the relatively difficult access to bnAb epitopes on spikes, including the proximity of variable regions and a high density of glycans. Yet, in a small proportion of HIV-infected individuals, potent bnAb responses do develop, and isolation of the corresponding monoclonal antibodies has been facilitated by identification of favorable donors with potent bnAb sera and by development of improved methods for human antibody generation. Molecular studies of recombinant Env trimers, alone and in interaction with bnAbs, are providing new insights that are fueling the development and testing of promising immunogens aimed at the elicitation of bnAbs.


Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Anti-VIH/metabolismo , Infecciones por VIH/inmunología , VIH/inmunología , Inmunización Pasiva/métodos , Virión/inmunología , Animales , Secuencia Conservada , Infecciones por VIH/prevención & control , Humanos , Evasión Inmune , Inmunización Pasiva/tendencias , Proteínas del Envoltorio Viral/inmunología
5.
Nat Immunol ; 25(7): 1245-1256, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38886592

RESUMEN

Human immunodeficiency virus (HIV) cure efforts are increasingly focused on harnessing CD8+ T cell functions, which requires a deeper understanding of CD8+ T cells promoting HIV control. Here we identifiy an antigen-responsive TOXhiTCF1+CD39+CD8+ T cell population with high expression of inhibitory receptors and low expression of canonical cytolytic molecules. Transcriptional analysis of simian immunodeficiency virus (SIV)-specific CD8+ T cells and proteomic analysis of purified CD8+ T cell subsets identified TOXhiTCF1+CD39+CD8+ T cells as intermediate effectors that retained stem-like features with a lineage relationship with terminal effector T cells. TOXhiTCF1+CD39+CD8+ T cells were found at higher frequency than TCF1-CD39+CD8+ T cells in follicular microenvironments and were preferentially located in proximity of SIV-RNA+ cells. Their frequency was associated with reduced plasma viremia and lower SIV reservoir size. Highly similar TOXhiTCF1+CD39+CD8+ T cells were detected in lymph nodes from antiretroviral therapy-naive and antiretroviral therapy-suppressed people living with HIV, suggesting this population of CD8+ T cells contributes to limiting SIV and HIV persistence.


Asunto(s)
Linfocitos T CD8-positivos , Ganglios Linfáticos , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Virus de la Inmunodeficiencia de los Simios/inmunología , Linfocitos T CD8-positivos/inmunología , Animales , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Ganglios Linfáticos/inmunología , Humanos , Macaca mulatta , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
6.
Nat Immunol ; 25(6): 1083-1096, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38816616

RESUMEN

Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region (MPER)-targeting bnAbs, such as 10E8, provide exceptionally broad neutralization, but some are autoreactive. Here, we generated humanized B cell antigen receptor knock-in mouse models to test whether a series of germline-targeting immunogens could drive MPER-specific precursors toward bnAbs. We found that recruitment of 10E8 precursors to germinal centers (GCs) required a minimum affinity for germline-targeting immunogens, but the GC residency of MPER precursors was brief due to displacement by higher-affinity endogenous B cell competitors. Higher-affinity germline-targeting immunogens extended the GC residency of MPER precursors, but robust long-term GC residency and maturation were only observed for MPER-HuGL18, an MPER precursor clonotype able to close the affinity gap with endogenous B cell competitors in the GC. Thus, germline-targeting immunogens could induce MPER-targeting antibodies, and B cell residency in the GC may be regulated by a precursor-competitor affinity gap.


Asunto(s)
Afinidad de Anticuerpos , Linfocitos B , Centro Germinal , Anticuerpos Anti-VIH , VIH-1 , Centro Germinal/inmunología , Animales , Ratones , Humanos , Linfocitos B/inmunología , VIH-1/inmunología , Anticuerpos Anti-VIH/inmunología , Afinidad de Anticuerpos/inmunología , Anticuerpos Neutralizantes/inmunología , Infecciones por VIH/inmunología , Vacunas contra el SIDA/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores de Antígenos de Linfocitos B/inmunología , Técnicas de Sustitución del Gen , Ratones Transgénicos , Anticuerpos ampliamente neutralizantes/inmunología , Ratones Endogámicos C57BL
7.
Nat Immunol ; 25(9): 1555-1564, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39179934

RESUMEN

Human immunodeficiency virus 1 (HIV-1) infection is characterized by a dynamic and persistent state of viral replication that overwhelms the host immune system in the absence of antiretroviral therapy (ART). The impact of prolonged treatment on the antiviral efficacy of HIV-1-specific CD8+ T cells has nonetheless remained unknown. Here, we used single-cell technologies to address this issue in a cohort of aging individuals infected early during the pandemic and subsequently treated with continuous ART. Our data showed that long-term ART was associated with a process of clonal succession, which effectively rejuvenated HIV-1-specific CD8+ T cell populations in the face of immune senescence. Tracking individual transcriptomes further revealed that initially dominant CD8+ T cell clonotypes displayed signatures of exhaustion and terminal differentiation, whereas newly dominant CD8+ T cell clonotypes displayed signatures of early differentiation and stemness associated with natural control of viral replication. These findings reveal a degree of immune resilience that could inform adjunctive treatments for HIV-1.


Asunto(s)
Linfocitos T CD8-positivos , Infecciones por VIH , VIH-1 , Replicación Viral , Linfocitos T CD8-positivos/inmunología , VIH-1/inmunología , VIH-1/fisiología , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Replicación Viral/efectos de los fármacos , Masculino , Persona de Mediana Edad , Femenino , Terapia Antirretroviral Altamente Activa , Antirretrovirales/uso terapéutico , Análisis de la Célula Individual , Diferenciación Celular/inmunología
8.
Nat Immunol ; 25(6): 1073-1082, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38816615

RESUMEN

A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.


Asunto(s)
Vacunas contra el SIDA , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , Proteína gp41 de Envoltorio del VIH , Infecciones por VIH , VIH-1 , Macaca mulatta , Animales , Humanos , Proteína gp41 de Envoltorio del VIH/inmunología , Anticuerpos Anti-VIH/inmunología , Ratones , Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/inmunología , VIH-1/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Vacunación , Anticuerpos ampliamente neutralizantes/inmunología , Linfocitos B/inmunología , Nanopartículas/química , Femenino , Regiones Determinantes de Complementariedad/inmunología , Epítopos/inmunología
9.
Cell ; 184(15): 3899-3914.e16, 2021 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-34237254

RESUMEN

The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.


Asunto(s)
Microbioma Gastrointestinal , Infecciones por VIH/inmunología , Infecciones por VIH/microbiología , Terapia Antirretroviral Altamente Activa , Biodiversidad , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Quimiocinas/sangre , Estudios de Cohortes , Glucólisis , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Humanos , Inflamación/genética , Inflamación/patología , Mitocondrias/metabolismo , Monocitos/metabolismo , Ácidos Nucleicos/sangre , Análisis de Componente Principal , Serratia/fisiología , Células TH1/inmunología , Células Th2/inmunología , Transcripción Genética , Uganda , Carga Viral/inmunología
10.
Cell ; 184(11): 2955-2972.e25, 2021 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-34019795

RESUMEN

Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , VIH-1/inmunología , Fragmentos Fab de Inmunoglobulinas/inmunología , Polisacáridos/inmunología , SARS-CoV-2/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Animales , Linfocitos B/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , COVID-19/inmunología , Dimerización , Epítopos/inmunología , Glicosilación , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Humanos , Fragmentos Fab de Inmunoglobulinas/química , Macaca mulatta , Polisacáridos/química , Receptores de Antígenos de Linfocitos B/química , Virus de la Inmunodeficiencia de los Simios/genética , Vacunas/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/química , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética
11.
Annu Rev Immunol ; 31: 705-42, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23330954

RESUMEN

A fascinating aspect of viral evolution relates to the ability of viruses to escape the adaptive immune response. The widely held view has been that the great variability of viral glycoproteins would be an absolute obstacle to the development of antibody-based therapies or vaccines that could confer broad and long-lasting protection. In the past five years, new approaches have been developed to interrogate human memory B cells and plasma cells with high efficiency and to isolate several broadly neutralizing antiviral antibodies against highly variable pathogens such as HIV-1 and influenza virus. These antibodies not only provide new tools for prophylaxis and therapy for viral diseases but also identify conserved epitopes that may be used to design new vaccines capable of conferring broader protection.


Asunto(s)
Anticuerpos Antivirales/fisiología , Pruebas de Neutralización/métodos , Animales , Anticuerpos Antivirales/uso terapéutico , Anticuerpos Anti-VIH/uso terapéutico , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Humanos , Inmunización Pasiva/métodos , Gripe Humana/inmunología , Gripe Humana/prevención & control , Gripe Humana/virología , Terapia Molecular Dirigida/métodos
12.
Annu Rev Immunol ; 31: 163-94, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23298212

RESUMEN

Natural killer (NK) cells are effector cells of the innate immune system and are important in the control of viral infections. Their relevance is reflected by the multiple mechanisms evolved by viruses to evade NK cell-mediated immune responses. Over recent years, our understanding of the interplay between NK cell immunity and viral pathogenesis has improved significantly. Here, we review the role of NK cells in the control of four important viral infections in humans: cytomegalovirus, influenza virus, HIV-1, and hepatitis C virus.


Asunto(s)
Células Asesinas Naturales/inmunología , Células Asesinas Naturales/virología , Virosis/inmunología , Virosis/virología , Animales , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/patología , Infecciones por Citomegalovirus/prevención & control , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Infecciones por VIH/prevención & control , Hepatitis C/inmunología , Hepatitis C/patología , Hepatitis C/prevención & control , Hepatitis Viral Animal/inmunología , Hepatitis Viral Animal/patología , Hepatitis Viral Animal/prevención & control , Humanos , Gripe Humana/inmunología , Gripe Humana/patología , Gripe Humana/prevención & control , Células Asesinas Naturales/patología , Virosis/patología
13.
Cell ; 180(3): 471-489.e22, 2020 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-32004464

RESUMEN

Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 µg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.


Asunto(s)
Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Sitios de Unión , Antígenos CD4/metabolismo , Células CHO , Estudios de Cohortes , Cricetulus , Epítopos/inmunología , Femenino , Células HEK293 , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Xenoinjertos , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Persona de Mediana Edad , Mutación , Unión Proteica/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética
14.
Cell ; 181(5): 1016-1035.e19, 2020 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-32413319

RESUMEN

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.


Asunto(s)
Células Epiteliales Alveolares/metabolismo , Enterocitos/metabolismo , Células Caliciformes/metabolismo , Interferón Tipo I/metabolismo , Mucosa Nasal/citología , Peptidil-Dipeptidasa A/genética , Adolescente , Células Epiteliales Alveolares/inmunología , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus/fisiología , COVID-19 , Línea Celular , Células Cultivadas , Niño , Infecciones por Coronavirus/virología , Enterocitos/inmunología , Células Caliciformes/inmunología , Infecciones por VIH/inmunología , Humanos , Gripe Humana/inmunología , Interferón Tipo I/inmunología , Pulmón/citología , Pulmón/patología , Macaca mulatta , Ratones , Mycobacterium tuberculosis , Mucosa Nasal/inmunología , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/virología , Receptores Virales/genética , SARS-CoV-2 , Serina Endopeptidasas/metabolismo , Análisis de la Célula Individual , Tuberculosis/inmunología , Regulación hacia Arriba
15.
Cell ; 178(1): 190-201.e11, 2019 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-31204101

RESUMEN

The placental transfer of maternal IgG is critical for infant protection against infectious pathogens. However, factors that modulate the placental transfer of IgG remain largely undefined. HIV-infected women have impaired placental IgG transfer, presenting a unique "disruption model" to define factors that modulate placental IgG transfer. We measured the placental transfer efficiency of maternal HIV and pathogen-specific IgG in US and Malawian HIV-infected mothers and their HIV-exposed uninfected and infected infants. We examined the role of maternal HIV disease progression, infant factors, placental Fc receptor expression, IgG subclass, and glycan signatures and their association with placental IgG transfer efficiency. Maternal IgG characteristics, such as binding to placentally expressed Fc receptors FcγRIIa and FcγRIIIa, and Fc region glycan profiles were associated with placental IgG transfer efficiency. Our findings suggest that Fc region characteristics modulate the selective placental transfer of IgG, with implications for maternal vaccine design and infant health.


Asunto(s)
Infecciones por VIH/transmisión , VIH/genética , Inmunoglobulina G/sangre , Transmisión Vertical de Enfermedad Infecciosa , Placenta/metabolismo , Complicaciones Infecciosas del Embarazo/virología , Receptores de IgG/metabolismo , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Glicosilación , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Fragmentos Fc de Inmunoglobulinas/metabolismo , Lactante , Recién Nacido , Malaui , Embarazo , Complicaciones Infecciosas del Embarazo/inmunología , Estados Unidos , Carga Viral/genética
16.
Cell ; 179(4): 880-894.e10, 2019 10 31.
Artículo en Inglés | MEDLINE | ID: mdl-31668804

RESUMEN

Current approaches to reducing the latent HIV reservoir entail first reactivating virus-containing cells to become visible to the immune system. A critical second step is killing these cells to reduce reservoir size. Endogenous cytotoxic T-lymphocytes (CTLs) may not be adequate because of cellular exhaustion and the evolution of CTL-resistant viruses. We have designed a universal CAR-T cell platform based on CTLs engineered to bind a variety of broadly neutralizing anti-HIV antibodies. We show that this platform, convertibleCAR-T cells, effectively kills HIV-infected, but not uninfected, CD4 T cells from blood, tonsil, or spleen and only when armed with anti-HIV antibodies. convertibleCAR-T cells also kill within 48 h more than half of the inducible reservoir found in blood of HIV-infected individuals on antiretroviral therapy. The modularity of convertibleCAR-T cell system, which allows multiplexing with several anti-HIV antibodies yielding greater breadth and control, makes it a promising tool for attacking the latent HIV reservoir.


Asunto(s)
Anticuerpos Antiidiotipos/farmacología , Infecciones por VIH/terapia , Inmunoterapia Adoptiva , Replicación Viral/genética , Animales , Anticuerpos Antiidiotipos/inmunología , Células HEK293 , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , VIH-1/patogenicidad , Humanos , Ratones , Tonsila Palatina/inmunología , Tonsila Palatina/metabolismo , Cultivo Primario de Células , Bazo/inmunología , Bazo/metabolismo , Linfocitos T Citotóxicos/inmunología , Latencia del Virus/inmunología , Replicación Viral/inmunología
17.
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
18.
Nat Immunol ; 22(4): 423-433, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33767427

RESUMEN

Individuals infected with human immunodeficiency virus type-1 (HIV-1) show metabolic alterations of CD4+ T cells through unclear mechanisms with undefined consequences. We analyzed the transcriptome of CD4+ T cells from patients with HIV-1 and revealed that the elevated oxidative phosphorylation (OXPHOS) pathway is associated with poor outcomes. Inhibition of OXPHOS by the US Food and Drug Administration-approved drug metformin, which targets mitochondrial respiratory chain complex-I, suppresses HIV-1 replication in human CD4+ T cells and humanized mice. In patients, HIV-1 peak viremia positively correlates with the expression of NLRX1, a mitochondrial innate immune receptor. Quantitative proteomics and metabolic analyses reveal that NLRX1 enhances OXPHOS and glycolysis during HIV-1-infection of CD4+ T cells to promote viral replication. At the mechanistic level, HIV infection induces the association of NLRX1 with the mitochondrial protein FASTKD5 to promote expression of mitochondrial respiratory complex components. This study uncovers the OXPHOS pathway in CD4+ T cells as a target for HIV-1 therapy.


Asunto(s)
Linfocitos T CD4-Positivos/virología , Genómica , Infecciones por VIH/virología , VIH-1/crecimiento & desarrollo , Metaboloma , Metabolómica , Fosforilación Oxidativa , Proteoma , Transcriptoma , Replicación Viral , Animales , Antivirales/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Modelos Animales de Enfermedad , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Células HEK293 , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/inmunología , VIH-1/metabolismo , Interacciones Huésped-Patógeno , Humanos , Células Jurkat , Masculino , Metformina/farmacología , Ratones , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Proteómica , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Carga Viral , Replicación Viral/efectos de los fármacos
19.
Annu Rev Immunol ; 29: 295-317, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21219175

RESUMEN

Multiple epidemiological studies have demonstrated associations between the human leukocyte antigen (HLA) loci and human immunodeficiency virus (HIV) disease, and more recently the killer cell immunoglobulin-like (KIR) locus has been implicated in differential responses to the virus. Genome-wide association studies have convincingly shown that the HLA class I locus is the most significant host genetic contributor to the variation in HIV control, underscoring a central role for CD8 T cells in resistance to the virus. However, both genetic and functional data indicate that part of the HLA effect on HIV is due to interactions between KIR and HLA genes, also implicating natural killer cells in defense against viral infection and viral expansion prior to initiation of an adaptive response. We review the HLA and KIR associations with HIV disease and the progress that has been made in understanding the mechanisms that explain these associations.


Asunto(s)
Infecciones por VIH/inmunología , VIH-1 , Antígenos HLA/inmunología , Receptores KIR/inmunología , Animales , Humanos , Linfocitos T/inmunología
20.
Cell ; 175(2): 387-399.e17, 2018 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-30270043

RESUMEN

HIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce with vaccines but are generated in ∼50% of HIV-1-infected individuals. Understanding the molecular mechanisms of host control of bnAb induction is critical to vaccine design. Here, we performed a transcriptome analysis of blood mononuclear cells from 47 HIV-1-infected individuals who made bnAbs and 46 HIV-1-infected individuals who did not and identified in bnAb individuals upregulation of RAB11FIP5, encoding a Rab effector protein associated with recycling endosomes. Natural killer (NK) cells had the highest differential expression of RAB11FIP5, which was associated with greater dysregulation of NK cell subsets in bnAb subjects. NK cells from bnAb individuals had a more adaptive/dysfunctional phenotype and exhibited impaired degranulation and cytokine production that correlated with RAB11FIP5 transcript levels. Moreover, RAB11FIP5 overexpression modulated the function of NK cells. These data suggest that NK cells and Rab11 recycling endosomal transport are involved in regulation of HIV-1 bnAb development.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Anticuerpos Neutralizantes/inmunología , Infecciones por VIH/inmunología , Vacunas contra el SIDA/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/fisiología , Adulto , Linfocitos B/inmunología , Línea Celular , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica/métodos , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/fisiopatología , VIH-1/patogenicidad , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/fisiología , Masculino , Persona de Mediana Edad
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