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[This corrects the article DOI: 10.3389/fimmu.2021.686240.].
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A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.
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COVID-19/inmunología , Microbioma Gastrointestinal/inmunología , Inflamación/inmunología , Intestinos/fisiología , SARS-CoV-2/fisiología , Femenino , Glicómica , Haptoglobinas/metabolismo , Humanos , Lipidómica , Masculino , Metabolómica , Persona de Mediana Edad , Permeabilidad , Precursores de Proteínas/metabolismo , Uniones Estrechas/metabolismoRESUMEN
Non-invasive biomarkers that predict HIV remission after antiretroviral therapy (ART) interruption are urgently needed. Such biomarkers can improve the safety of analytic treatment interruption (ATI) and provide mechanistic insights into the host pathways involved in post-ART HIV control. Here we report plasma glycomic and metabolic signatures of time-to-viral-rebound and probability-of-viral-remission using samples from two independent cohorts. These samples include a large number of post-treatment controllers, a rare population demonstrating sustained virologic suppression after ART-cessation. These signatures remain significant after adjusting for key demographic and clinical confounders. We also report mechanistic links between some of these biomarkers and HIV latency reactivation and/or myeloid inflammation in vitro. Finally, machine learning algorithms, based on selected sets of these biomarkers, predict time-to-viral-rebound with 74% capacity and probability-of-viral-remission with 97.5% capacity. In summary, we report non-invasive plasma biomarkers, with potential functional significance, that predict both the duration and probability of HIV remission after treatment interruption.
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Biomarcadores/sangre , Infecciones por VIH/sangre , Privación de Tratamiento , Adulto , Antirretrovirales/administración & dosificación , Estudios de Cohortes , ADN Viral/sangre , Femenino , Glicómica , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Inflamación , Macrófagos/inmunología , Masculino , Metabolómica , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , ARN Viral/sangre , Activación ViralRESUMEN
While CD19-directed chimeric antigen receptor (CAR) T cells can induce remission in patients with B cell acute lymphoblastic leukemia (ALL), a large subset relapse with CD19- disease. Like CD19, CD22 is broadly expressed by B-lineage cells and thus serves as an alternative immunotherapy target in ALL. Here we present the composite outcomes of two pilot clinical trials ( NCT02588456 and NCT02650414 ) of T cells bearing a 4-1BB-based, CD22-targeting CAR in patients with relapsed or refractory ALL. The primary end point of these studies was to assess safety, and the secondary end point was antileukemic efficacy. We observed unexpectedly low response rates, prompting us to perform detailed interrogation of the responsible CAR biology. We found that shortening of the amino acid linker connecting the variable heavy and light chains of the CAR antigen-binding domain drove receptor homodimerization and antigen-independent signaling. In contrast to CD28-based CARs, autonomously signaling 4-1BB-based CARs demonstrated enhanced immune synapse formation, activation of pro-inflammatory genes and superior effector function. We validated this association between autonomous signaling and enhanced function in several CAR constructs and, on the basis of these observations, designed a new short-linker CD22 single-chain variable fragment for clinical evaluation. Our findings both suggest that tonic 4-1BB-based signaling is beneficial to CAR function and demonstrate the utility of bedside-to-bench-to-bedside translation in the design and implementation of CAR T cell therapies.
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Ligando 4-1BB/metabolismo , Inmunoterapia Adoptiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores Quiméricos de Antígenos/metabolismo , Lectina 2 Similar a Ig de Unión al Ácido Siálico/metabolismo , Linfocitos T/trasplante , Adulto , Animales , Antígenos CD19/metabolismo , Linfocitos B/inmunología , Antígenos CD28/genética , Células Cultivadas , Niño , Preescolar , Femenino , Humanos , Masculino , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Linfocitos T/inmunología , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Accurate characterization of the human immunodeficiency virus (HIV) reservoir is imperative to develop an effective cure. HIV was measured in antiretroviral therapy-suppressed individuals using the intact proviral DNA assay (IPDA), along with assays for total or integrated HIV DNA, and inducible HIV RNA or p24. Intact provirus correlated with total and integrated HIV.
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Infecciones por VIH , VIH-1 , Linfocitos T CD4-Positivos , ADN Viral/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Provirus/genética , Latencia del VirusRESUMEN
BACKGROUND: A comprehensive understanding of host factors modulated by the antiviral cytokine interferon-α (IFNα) is imperative for harnessing its beneficial effects while avoiding its detrimental side-effects during HIV infection. Cytokines modulate host glycosylation which plays a critical role in mediating immunological functions. However, the impact of IFNα on host glycosylation has never been characterized. METHODS: We assessed the impact of pegylated IFNα2a on IgG glycome, as well as CD8+ T and NK cell-surface glycomes, of 18 HIV-infected individuals on suppressive antiretroviral therapy. We linked these glycomic signatures to changes in inflammation, CD8+ T and NK cell phenotypes, and HIV DNA. FINDINGS: We identified significant interactions that support a model in which a) IFNα increases the proportion of pro-inflammatory, bisecting GlcNAc glycans (known to enhance FcγR binding) within the IgG glycome, which in turn b) increases inflammation, which c) leads to poor CD8+ T cell phenotypes and poor IFNα-mediated reduction of HIV DNA. Examining cell-surface glycomes, IFNα increases levels of the immunosuppressive GalNAc-containing glycans (T/Tn antigens) on CD8+ T cells. This induction is associated with lower HIV-gag-specific CD8+ T cell functions. Last, IFNα increases levels of fucose on NK cells. This induction is associated with higher NK functions upon K562 stimulation. INTERPRETATION: IFNα causes host glycomic alterations that are known to modulate immunological responses. These alterations are associated with both detrimental and beneficial consequences of IFNα. Manipulating host glycomic interactions may represent a strategy for enhancing the positive effects of IFNα while avoiding its detrimental side-effects. FUNDING: NIH grants R21AI143385, U01AI110434.
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Antivirales/farmacología , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Interferón-alfa/farmacología , Terapia Antirretroviral Altamente Activa , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Citocinas/metabolismo , Glicosilación/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Mediadores de Inflamación/metabolismo , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Recuento de Linfocitos , Polisacáridos/metabolismoRESUMEN
OBJECTIVE: Glycosylation plays a critical role in mediating several antibody (mainly immunoglobulin G; IgG) immunological functions, including antibody-dependent cell-mediated cytotoxicity (ADCC), and anti-inflammatory activities. We investigated whether IgG glycosylation and immune profile patterns are differentially modulated in mono and dual infection using samples from untreated hepatitis C virus (HCV)-infected individuals with and without co-infection with antiretroviral therapy (ART)-suppressed HIV. DESIGN: IgG glycosylation, immune subsets, natural killer cell function, and liver enzymes were assessed in 14 HCV mono-infected and 27 ART-suppressed HIV/HCV co-infected participants naïve to HCV treatment. Historic IgG glycosylation data from 23 ART-suppressed chronically HIV-infected individuals were also used for comparisons. METHODS: Plasma IgG glycosylation was assessed using capillary electrophoresis. Whole blood was used for immune subset characterization by flow cytometry. Peripheral blood mononuclear cells were used to measure constitutive and interferon-α-induced K562 target cell lysis. Statistical analysis was performed using R (3.5.0). RESULTS: HIV/HCV had lower levels of pro-ADCC-associated nonfucosylated glycans when compared with HIV [e.g. di-sialylated A2 percentage (%): Pâ=â0.04], and higher levels of T and myeloid cell activation/exhaustion when compared with HCV (e.g. CD3CD8CD38 %: Pâ<â0.001). Finally, in HCV high levels of the anti-inflammatory galactosylated and sialylated glycans were associated with low plasma levels of aspartate aminotransferase (AST), low CD8 T-cell activation, and high CD8 T-cell exhaustion. CONCLUSION: HCV modulates IgG glycosylation profile in HIV co-infected individuals on suppressive ART. These results could inform on the modulation of IgG glycans in other mono and dual infections.
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Coinfección , Infecciones por VIH , Hepatitis C , Inmunoglobulina G/química , Fármacos Anti-VIH/uso terapéutico , Coinfección/inmunología , Coinfección/virología , Glicosilación , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Hepacivirus/inmunología , Hepatitis C/complicaciones , Hepatitis C/inmunología , Humanos , Leucocitos MononuclearesRESUMEN
An emerging paradigm suggests that gut glycosylation is a key force in maintaining the homeostatic relationship between the gut and its microbiota. Nevertheless, it is unclear how gut glycosylation contributes to the HIV-associated microbial translocation and inflammation that persist despite viral suppression and contribute to the development of several comorbidities. We examined terminal ileum, right colon, and sigmoid colon biopsies from HIV-infected virally-suppressed individuals and found that gut glycomic patterns are associated with distinct microbial compositions and differential levels of chronic inflammation and HIV persistence. In particular, high levels of the pro-inflammatory hypo-sialylated T-antigen glycans and low levels of the anti-inflammatory fucosylated glycans were associated with higher abundance of glycan-degrading microbial species (in particular, Bacteroides vulgatus), a less diverse microbiome, higher levels of inflammation, and higher levels of ileum-associated HIV DNA. These findings are linked to the activation of the inflammasome-mediating eIF2 signaling pathway. Our study thus provides the first proof-of-concept evidence that a previously unappreciated factor, gut glycosylation, is a force that may impact the vicious cycle between HIV infection, microbial translocation, and chronic inflammation.
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Factor 2 Eucariótico de Iniciación/metabolismo , Microbioma Gastrointestinal , Infecciones por VIH/metabolismo , Inflamasomas/metabolismo , Transducción de Señal , Terapia Antirretroviral Altamente Activa , Biodiversidad , Colon Sigmoide/inmunología , Colon Sigmoide/metabolismo , Colon Sigmoide/microbiología , Disbiosis , Epítopos de Linfocito T/inmunología , Microbioma Gastrointestinal/inmunología , Glicosilación , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Huésped Inmunocomprometido , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Metagenoma , Metagenómica/métodos , Procesamiento Proteico-Postraduccional , Carga ViralRESUMEN
OBJECTIVE: HIV cure research urgently needs to identify pre-analytic treatment interruption (ATI) biomarkers of time-to-viral-rebound and viral setpoint to mitigate the risk of ATI and accelerate development of a cure. We previously reported that galactosylated IgG glycans, G2, negatively correlate with cell-associated HIV DNA and RNA during antiretroviral therapy (ART). We hypothesized that this and other plasma glycomic traits can predict time-to-viral-rebound and viral setpoint upon ART cessation. DESIGN: We profiled the circulating glycomes (plasma and bulk IgG) of two geographically distinct cohorts: Philadelphia Cohort - 24 HIV-infected, ART-suppressed individuals who had participated in an open-ended ATI study without concurrent immunomodulatory agents. Johannesburg Cohort - 23 HIV-infected, ART-suppressed individuals who had participated in a 2-week ATI. METHODS: Capillary electrophoresis and lectin microarray were used for glycomic analyses. Cox proportional-hazards model and log-rank test were used for statistical analyses. RESULTS: Higher pre-ATI levels of the IgG glycan, G2, were significantly associated with a longer time-to-viral-rebound (hazard ratioâ=â0.12, Pâ=â0.05). In addition to G2, we identified several predictive glycomic traits in plasma, for example, levels of FA2BG1, a non-sialylated, core-fucosylated glycan, associated with a longer time-to-viral-rebound (hazard ratioâ=â0.023, Pâ=â0.05), whereas FA2G2S1, a sialylated glycan, associated with a shorter time-to-viral-rebound (hazard ratioâ=â24.1, Pâ=â0.028). Additionally, pre-ATI plasma glycomic signatures associated with a lower viral setpoint, for example, T-antigen (Galß1-3GalNAc) (râ=â0.75, Pâ=â0.0007), or a higher viral setpoint, for example, polylactosamine (râ=â-0.58, Pâ=â0.01). These results were initially validated in the Johannesburg Cohort. CONCLUSION: We describe first-in-class, non-invasive, plasma and IgG glycomic biomarkers that inform time-to-viral-rebound and viral setpoint in two geographically distinct cohorts.