ABSTRACT
Gastrointestinal (GI) B cells and plasma cells (PCs), critical to mucosal homeostasis, play an important role in the host response to HIV-1 infection. Here, high resolution mapping of human B cells and PCs from colon and ileum during both viremic and suppressed HIV-1 infection identified a significant reduction in germinal center (GC) B cells and Follicular Dendritic Cells (FDCs) during HIV-1 viremia. Further, IgA + PCs, the major cellular output of intestinal GCs were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling persisted in antiretroviral therapy (ART) treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations associated with changes in intestinal microbiome composition and systemic inflammation. Herein, we highlight a key immune defect in the GI mucosa due to HIV-1 viremia, with major implications. One Sentence Summary: Major perturbations in intestinal GC dynamics in viremic HIV-1 infection relate to reduced IgA + plasma cells, systemic inflammation and microbiota changes.
ABSTRACT
Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4ß7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (ß7+) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4ß7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of ß7+IgG+ plasmablasts in circulation, as well as IgG+ plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4ß7-targeted therapies, with major implications for this therapeutic paradigm in UC.
Subject(s)
Colitis, Ulcerative , Humans , Animals , Mice , Colitis, Ulcerative/drug therapy , Integrins , Intestinal Mucosa , Peyer's Patches , Immunoglobulin G/therapeutic useABSTRACT
More than 40 years after the first reported cases of what then became known as acquired immunodeficiency syndrome (AIDS), tremendous progress has been achieved in transforming the disease from almost universally fatal to a chronic manageable condition. Nonetheless, the efforts to find a preventative vaccine or a cure for the underlying infection with Human Immunodeficiency Virus (HIV) remain largely unsuccessful. Many challenges intrinsic to the virus characteristics and host response need to be overcome for either goal to be achieved. This article will review the obstacles to an effective HIV cure, specifically the steps involved in the generation of HIV latency, focusing on the role of the gut-associated lymphoid tissue, which has received less attention compared with the peripheral blood, despite being the largest repository of lymphoid tissue in the human body, and a large site for HIV persistence.
ABSTRACT
Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon with sharply rising global prevalence. Dysfunctional epithelial compartment (EC) dynamics are implicated in UC pathogenesis although EC-specific studies are sparse. Applying orthogonal high-dimensional EC profiling to a Primary Cohort (PC; n=222), we detail major epithelial and immune cell perturbations in active UC. Prominently, reduced frequencies of mature BEST4+OTOP2+ absorptive and BEST2+WFDC2+ secretory epithelial enterocytes were associated with the replacement of homeostatic, resident TRDC+KLRD1+HOPX+ γδ+ T cells with RORA+CCL20+S100A4+ TH17 cells and the influx of inflammatory myeloid cells. The EC transcriptome (exemplified by S100A8, HIF1A, TREM1, CXCR1) correlated with clinical, endoscopic, and histological severity of UC in an independent validation cohort (n=649). Furthermore, therapeutic relevance of the observed cellular and transcriptomic changes was investigated in 3 additional published UC cohorts (n=23, 48 and 204 respectively) to reveal that non-response to anti-Tumor Necrosis Factor (anti-TNF) therapy was associated with EC related myeloid cell perturbations. Altogether, these data provide high resolution mapping of the EC to facilitate therapeutic decision-making and personalization of therapy in patients with UC.
ABSTRACT
Targeting the α4ß7-MAdCAM-1 axis with vedolizumab (VDZ) is a front-line therapeutic paradigm in ulcerative colitis (UC). However, mechanism(s) of action (MOA) of VDZ remain relatively undefined. Here, we examined three distinct cohorts of patients with UC (n=83, n=60, and n=21), to determine the effect of VDZ on the mucosal and peripheral immune system. Transcriptomic studies with protein level validation were used to study drug MOA using conventional and transgenic murine models. We found a significant decrease in colonic and ileal naïve B and T cells and circulating gut-homing plasmablasts (ß7+) in VDZ-treated patients, pointing to gut-associated lymphoid tissue (GALT) targeting by VDZ. Murine Peyer's patches (PP) demonstrated a significant loss cellularity associated with reduction in follicular B cells, including a unique population of epithelium-associated B cells, following anti-α4ß7 antibody (mAb) administration. Photoconvertible (KikGR) mice unequivocally demonstrated impaired cellular entry into PPs in anti-α4ß7 mAb treated mice. In VDZ-treated, but not anti-tumor necrosis factor-treated UC patients, lymphoid aggregate size was significantly reduced in treatment responders compared to non-responders, with an independent validation cohort further confirming these data. GALT targeting represents a novel MOA of α4ß7-targeted therapies, with major implications for this therapeutic paradigm in UC, and for the development of new therapeutic strategies.
ABSTRACT
B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n = 145; validation cohort 1, n = 664; and validation cohort 2, n = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG+ plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvß6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis.
Subject(s)
Colitis, Ulcerative , Plasma Cells , B-Lymphocytes , Colitis, Ulcerative/genetics , Humans , Intestinal Mucosa/pathology , Lymphocyte Count , T-Lymphocytes, Helper-InducerABSTRACT
Gastrointestinal symptoms are common in COVID-19 patients but the nature of the gut immune response to SARS-CoV-2 remains poorly characterized, partly due to the difficulty of obtaining biopsy specimens from infected individuals. In lieu of tissue samples, we measured cytokines, inflammatory markers, viral RNA, microbiome composition, and antibody responses in stool samples from a cohort of 44 hospitalized COVID-19 patients. SARS-CoV-2 RNA was detected in stool of 41% of patients and more frequently in patients with diarrhea. Patients who survived had lower fecal viral RNA than those who died. Strains isolated from stool and nasopharynx of an individual were the same. Compared to uninfected controls, COVID-19 patients had higher fecal levels of IL-8 and lower levels of fecal IL-10. Stool IL-23 was higher in patients with more severe COVID-19 disease, and we found evidence of intestinal virus-specific IgA responses associated with more severe disease. We provide evidence for an ongoing humeral immune response to SARS-CoV-2 in the gastrointestinal tract, but little evidence of overt inflammation.
Subject(s)
COVID-19 , Feces , Gastrointestinal Microbiome , Nasopharynx/virology , RNA, Viral/isolation & purification , Aged , Biomarkers/metabolism , COVID-19/epidemiology , COVID-19/immunology , Cohort Studies , Cytokines/metabolism , Feces/virology , Female , Humans , Immunoglobulin A/blood , Immunoglobulin A/immunology , Male , Middle Aged , New York City/epidemiology , SARS-CoV-2/isolation & purificationABSTRACT
BACKGROUND & AIMS: Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance. METHODS: Human intestinal biopsy tissues were obtained from patients with COVID-19 (n = 19) and uninfected control individuals (n = 10) for microscopic examination, cytometry by time of flight analyses, and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in 2 large, independent cohorts of hospitalized patients in the United States (N = 634) and Europe (N = 287) using multivariate logistic regressions. RESULTS: COVID-19 case patients and control individuals in the biopsy cohort were comparable for age, sex, rates of hospitalization, and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy in 15 of 17 patients studied. High-dimensional analyses of GI tissues showed low levels of inflammation, including down-regulation of key inflammatory genes including IFNG, CXCL8, CXCL2, and IL1B and reduced frequencies of proinflammatory dendritic cells compared with control individuals. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of sex, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms. CONCLUSIONS: These data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in patients with COVID-19 presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2-associated inflammation needs to be further examined.
Subject(s)
COVID-19/virology , Gastrointestinal Diseases/virology , Immunity, Mucosal , Intestinal Mucosa/virology , SARS-CoV-2/pathogenicity , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/immunology , COVID-19/mortality , Case-Control Studies , Cells, Cultured , Cytokines/blood , Female , Gastrointestinal Diseases/diagnosis , Gastrointestinal Diseases/immunology , Gastrointestinal Diseases/mortality , Host-Pathogen Interactions , Humans , Inflammation Mediators/blood , Intestinal Mucosa/immunology , Italy , Male , Middle Aged , New York City , Prognosis , Risk Assessment , Risk Factors , SARS-CoV-2/immunology , Viral LoadABSTRACT
Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of coronavirus disease 2019 (COVID-19), we investigated intestinal infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its effect on disease pathogenesis. SARS-CoV-2 was detected in small intestinal enterocytes by immunofluorescence staining or electron microscopy, in 13 of 15 patients studied. High dimensional analyses of GI tissues revealed low levels of inflammation in general, including active downregulation of key inflammatory genes such as IFNG, CXCL8, CXCL2 and IL1B and reduced frequencies of proinflammatory dendritic cell subsets. To evaluate the clinical significance of these findings, examination of two large, independent cohorts of hospitalized patients in the United States and Europe revealed a significant reduction in disease severity and mortality that was independent of gender, age, and examined co-morbid illnesses. The observed mortality reduction in COVID-19 patients with GI symptoms was associated with reduced levels of key inflammatory proteins including IL-6, CXCL8, IL-17A and CCL28 in circulation but was not associated with significant differences in nasopharyngeal viral loads. These data draw attention to organ-level heterogeneity in disease pathogenesis and highlight the role of the GI tract in attenuating SARS-CoV-2-associated inflammation with related mortality benefit. ONE SENTENCE SUMMARY: Intestinal infection with SARS-CoV-2 is associated with a mild inflammatory response and improved clinical outcomes.
ABSTRACT
We sought to characterize the role of the gastrointestinal immune system in the pathogenesis of the inflammatory response associated with COVID-19. We measured cytokines, inflammatory markers, viral RNA, microbiome composition and antibody responses in stool from a cohort of 44 hospitalized COVID-19 patients. SARS-CoV-2 RNA was detected in stool of 41% of patients and more frequently in patients with diarrhea. Patients who survived had lower fecal viral RNA than those who died. Strains isolated from stool and nasopharynx of an individual were the same. Compared to uninfected controls, COVID-19 patients had higher fecal levels of IL-8 and lower levels of fecal IL-10. Stool IL-23 was higher in patients with more severe COVID-19 disease, and we found evidence of intestinal virus-specific IgA responses associated with more severe disease. We provide evidence for an ongoing humeral immune response to SARS-CoV-2 in the gastrointestinal tract, but little evidence of overt inflammation.
ABSTRACT
BACKGROUND: There are limited data regarding the clinical impact of coronavirus disease 2019 (COVID-19) on people living with human immunodeficiency virus (PLWH). In this study, we compared outcomes for PLWH with COVID-19 to a matched comparison group. METHODS: We identified 88 PLWH hospitalized with laboratory-confirmed COVID-19 in our hospital system in New York City between 12 March and 23 April 2020. We collected data on baseline clinical characteristics, laboratory values, HIV status, treatment, and outcomes from this group and matched comparators (1 PLWH to up to 5 patients by age, sex, race/ethnicity, and calendar week of infection). We compared clinical characteristics and outcomes (death, mechanical ventilation, hospital discharge) for these groups, as well as cumulative incidence of death by HIV status. RESULTS: Patients did not differ significantly by HIV status by age, sex, or race/ethnicity due to the matching algorithm. PLWH hospitalized with COVID-19 had high proportions of HIV virologic control on antiretroviral therapy. PLWH had greater proportions of smoking (P < .001) and comorbid illness than uninfected comparators. There was no difference in COVID-19 severity on admission by HIV status (P = .15). Poor outcomes for hospitalized PLWH were frequent but similar to proportions in comparators; 18% required mechanical ventilation and 21% died during follow-up (compared with 23% and 20%, respectively). There was similar cumulative incidence of death over time by HIV status (P = .94). CONCLUSIONS: We found no differences in adverse outcomes associated with HIV infection for hospitalized COVID-19 patients compared with a demographically similar patient group.
Subject(s)
COVID-19 , Coronavirus , HIV Infections , COVID-19/mortality , COVID-19/therapy , HIV , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Humans , New York City/epidemiology , Patient Discharge , Respiration, Artificial , SARS-CoV-2 , Treatment OutcomeABSTRACT
Individuals with a negative HIV test before a positive one (seroconverters) may represent missed opportunities for prevention. To inform HIV prevention strategies, we aimed to characterize patients who seroconverted despite accessing care. We identified patients at a large, urban healthcare system who seroconverted between 2009 and 2014. Demographics, visits, and HIV-related variables were extracted from the medical records. We performed descriptive statistics, assessed for trends, and tested for associations according to sex. 220 seroconverters were identified: 45% were female, 87% were non-Hispanic Black or Hispanic, and median number of negative tests prior to diagnosis was 2 (IQR 1-3). Overall, 49% reported heterosexual contact as their risk factor and the proportion with heterosexual risk increased over time (24% in 2009 vs. 56% in 2014, p = 0.03). Compared to men, women were older at the time of diagnosis (35 vs. 26 years old, p < 0.01), had more visits between their latest negative and positive HIV test (4 vs. 2, p < 0.01), and were more likely to be diagnosed in the context of screening (64% vs. 56%, p = 0.05). We identified a population that became HIV-infected despite multiple healthcare encounters and undergoing HIV testing multiple times. Patients were mostly heterosexual and almost half were female. To avoid missed opportunities for those already accessing care, HIV prevention efforts should include strategies tailored to individuals with less frequently recognized risk profiles.
Subject(s)
AIDS Serodiagnosis/statistics & numerical data , HIV Infections/prevention & control , Health Services Accessibility , Heterosexuality , Adult , Early Diagnosis , Female , HIV Infections/diagnosis , HIV Infections/epidemiology , Hispanic or Latino , Homosexuality, Male , Humans , Male , Medical Records , Middle Aged , New York , Retrospective Studies , Risk FactorsABSTRACT
Hydrogen peroxide ingestion can cause gastric irritation and gas embolism; however, most reported cases are from the highly concentrated (≥35%) solution used in the industry and data on household-used 3% solution ingestion is scarce. We report a case of a portal vein gas embolism after ingestion of 3% hydrogen peroxide. The patient was managed conservatively with antacids and improved in 48 hours. Endoscopy and hyperbaric treatment were considered but not pursued. This is the fifth reported case of gas embolism after 3% hydrogen peroxide ingestion and stands in line with other reports where the patients improved with conservative management.
ABSTRACT
BACKGROUND: Statin use is associated with a modest increase in the incidence of type 2 diabetes mellitus (DM) among the general population. However, HIV-infected patients have a higher risk of developing DM, and it is unclear whether statins have a diabetogenic effect in these patients. Therefore, we investigated the associations of statin use and exposure to antiretroviral drugs with type 2 DM onset in a cohort of HIV-infected patients. METHODS: This retrospective, controlled, cohort study identified HIV-1-infected patients who did not have DM and were not receiving statins at their antiretroviral treatment (ART) initiation. Follow-up was accrued from ART initiation to the earliest instance of a DM diagnosis, loss to follow-up, death, or last available visit. The incidence of DM was estimated according to statin use, which was adjusted for periods without statin treatment. The Fine-Gray competing risk model was used in the multivariate analysis to identify risk factors for developing DM. RESULTS: The analyses evaluated 6,195 patients followed for 9.8 years (interquartile range: 4.3-16.3 years). During 64,149 person-years of follow-up (PYFU), 235 patients developed DM (crude incidence: 3.66 [95%CI: 3.20-4.13] per 1,000 PYFU), and 917 (14%) patients used statins. After adjusting for potential confounders, statin use was associated with a non-significant increase in the risk of DM (AHR: 1.21, 95% CI: 0.71-2.07; P = 0.47). DM was more likely among patients who were ever treated with stavudine, and less likely among those ever treated using emtricitabine, tenofovir, abacavir, efavirenz, nevirapine, atazanavir or darunavir. CONCLUSIONS: A higher risk of diabetes mellitus was not associated with statin treatment but with traditional risk factors and stavudine use while a reduced risk of DM was associated with the use of emtricitabine, tenofovir, abacavir, efavirenz, nevirapine, atazanavir or darunavir.
Subject(s)
Anti-HIV Agents/therapeutic use , Diabetes Mellitus, Type 2/etiology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Adult , Cohort Studies , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/prevention & control , Diabetes Mellitus, Type 2/virology , Female , Follow-Up Studies , HIV Infections/drug therapy , HIV-1/pathogenicity , Humans , Italy/epidemiology , Male , Middle Aged , Retrospective Studies , Risk FactorsSubject(s)
Acetanilides/adverse effects , Coronary Restenosis/drug therapy , Electrocardiography/drug effects , Long QT Syndrome/chemically induced , Piperazines/adverse effects , Takotsubo Cardiomyopathy/drug therapy , Acetanilides/therapeutic use , Action Potentials/drug effects , Chest Pain/diagnosis , Chest Pain/drug therapy , Coronary Angiography/methods , Coronary Restenosis/diagnostic imaging , Coronary Stenosis/diagnostic imaging , Coronary Stenosis/therapy , Female , Follow-Up Studies , Heart Conduction System/drug effects , Humans , Long QT Syndrome/diagnosis , Middle Aged , Piperazines/therapeutic use , Ranolazine , Risk Assessment , Sodium Channel Blockers/adverse effects , Sodium Channel Blockers/therapeutic use , Stents , Takotsubo Cardiomyopathy/diagnosisABSTRACT
OBJECTIVE: Previous studies have shown that statins use is associated with a lower mortality risk or occurrence of non-Hodgkin's lymphoma or non-AIDS-defining malignancies (NADMs) in HIV-positive patients. We evaluated the effect of statin therapy on the occurrence of all AIDS-defining malignancy (ADM) and NADM among HIV-positive patients. DESIGN: A chart study on HIV-1 infected patients attending the Infectious Diseases Department of the San Raffaele Scientific Institute, Italy. METHODS: Incident malignancies diagnosed since antiretroviral treatment (ART) initiation until October 2012 among treated patients not taking statins at ART initiation. Statin therapy had to precede cancer diagnosis, if it occurred. Malignancies that occurred before ART or statin initiation were excluded. Follow-up was calculated since ART initiation until the first cancer diagnosis or loss to follow-up or death or last available visit, whichever occurred first. Results are described as median (interquartile range, IQR). RESULTS: Five thousand, three hundred and fifty-seven HIV-1 treated patients were included. During 52â663 person-years, 740 (14%) patients had a history of statin use; 375 malignancies occurred: 12 (1.6%) malignancies (0 ADM; 12 NADM, crude incidence rate, 1.3/1000 person-years) among statin users and 363 (7.9%) malignancies (194 ADM; 169 NADM, crude incidence rate, 8.4/1000 person-years) among non-statin users. By multivariate Fine-Gray regression, statin use was associated with a lower risk of cancer [adjusted hazard ratio (95% confidence interval) for ever use: 0.45 (0.17-0.71)]. CONCLUSION: Among HIV-1 treated patients, statin use was associated with a lower risk of cancer; the benefit was mainly related to AIDS-defining malignancies. Confirmatory studies are needed to consider the residual confounding likely present in this study.
Subject(s)
Anti-Retroviral Agents/therapeutic use , Anticholesteremic Agents/therapeutic use , HIV Infections/complications , HIV Infections/drug therapy , Neoplasms/epidemiology , Adult , Female , HIV Infections/virology , HIV-1/isolation & purification , Humans , Incidence , Italy/epidemiology , Male , Middle Aged , Risk AssessmentABSTRACT
BACKGROUND: The objective of this study was to compare immunologic, virologic, and clinical outcomes between living human immunodeficiency virus (HIV)-infected individuals who had a diagnosis of lymphoma versus outcomes in a control group of cancer-free, HIV-infected patients. METHODS: In this matched cohort study, patients in the case group were survivors of incident lymphomas that occurred between 1997 and June 2010. Controls were living, cancer-free, HIV-infected patients who were matched to cases at a 4:1 ratio by age, sex, nadir CD4 cell count, and year of HIV diagnosis. The date of lymphoma diagnosis served as the baseline in cases and in the corresponding controls. RESULTS: In total, 62 patients (cases) who had lymphoma (20 with Hodgkin disease [HD] and 42 with non-Hodgkin lymphoma [NHL]) were compared with 211 controls. The overall median follow-up was 4.8 years (interquartile range, 2.0-7.9 years). The CD4 cell count at baseline was 278 cells/mm³ (interquartile range, 122-419 cells/mm³) in cases versus 421 cells/mm³ (interquartile range, 222-574 cells/mm³) in controls (P = .003). At the last available visit, the CD4 cell count was 412 cells/mm³ (range, 269-694 cells/mm³) in cases versus 518 cells/mm³ (interquartile range, 350-661 cells/mm³) in controls (P = .087). The proportion of patients who achieved virologic success increased from 30% at baseline to 74% at the last available visit in cases (P = .008) and from 51% to 81% in controls (P = .0286). Patients with HD reached higher CD4 cell counts at their last visit than patients with NHL (589 cells/mm³ [range, 400-841 cells/mm³] vs 332 cells/mm³ [interquartile range, 220-530 cells/mm³], respectively; P = .003). Virologic success was similar between patients with HD and patients with NHL at the last visit. Forty cases (65%) and 76 controls (36%) experienced at least 1 clinical event after baseline (P < .0001); cases were associated with a shorter time to occurrence of the first clinical event compared with controls (P < .0001). CONCLUSIONS: HIV-infected lymphoma survivors experienced more clinical events than controls, especially during the first year of follow-up, but they reached similar long-term immunologic and virologic outcomes.