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Barry H, Lhomme E, Surénaud M, Nouctara M, Robinson C, Bockstal V, Valea I, Somda S, Tinto H, Meda N, Greenwood B, Thiébaut R, Lacabaratz C. Helminth exposure and immune response to the two-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen. PLoS Negl Trop Dis 2024; 18:e0011500. [PMID: 38603720 PMCID: PMC11037528 DOI: 10.1371/journal.pntd.0011500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 04/23/2024] [Accepted: 02/28/2024] [Indexed: 04/13/2024] Open
Abstract
BACKGROUND The exposure to parasites may influence the immune response to vaccines in endemic African countries. In this study, we aimed to assess the association between helminth exposure to the most prevalent parasitic infections, schistosomiasis, soil transmitted helminths infection and filariasis, and the Ebola virus glycoprotein (EBOV GP) antibody concentration in response to vaccination with the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen in African and European participants using samples obtained from three international clinical trials. METHODS/PRINCIPAL FINDINGS We conducted a study in a subset of participants in the EBL2001, EBL2002 and EBL3001 clinical trials that evaluated the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against EVD in children, adolescents and adults from the United Kingdom, France, Burkina Faso, Cote d'Ivoire, Kenya, Uganda and Sierra Leone. Immune markers of helminth exposure at baseline were evaluated by ELISA with three commercial kits which detect IgG antibodies against schistosome, filarial and Strongyloides antigens. Luminex technology was used to measure inflammatory and activation markers, and Th1/Th2/Th17 cytokines at baseline. The association between binding IgG antibodies specific to EBOV GP (measured on day 21 post-dose 2 and on Day 365 after the first dose respectively), and helminth exposure at baseline was evaluated using a multivariable linear regression model adjusted for age and study group. Seventy-eight (21.3%) of the 367 participants included in the study had at least one helminth positive ELISA test at baseline, with differences of prevalence between studies and an increased prevalence with age. The most frequently detected antibodies were those to Schistosoma mansoni (10.9%), followed by Acanthocheilonema viteae (9%) and then Strongyloides ratti (7.9%). Among the 41 immunological analytes tested, five were significantly (p < .003) lower in participants with at least one positive helminth ELISA test result: CCL2/MCP1, FGFbasic, IL-7, IL-13 and CCL11/Eotaxin compared to participants with negative helminth ELISA tests. No significant association was found with EBOV-GP specific antibody concentration at 21 days post-dose 2, or at 365 days post-dose 1, adjusted for age group, study, and the presence of any helminth antibodies at baseline. CONCLUSIONS/SIGNIFICANCE No clear association was found between immune markers of helminth exposure as measured by ELISA and post-vaccination response to the Ebola Ad26.ZEBOV/ MVA-BN-Filo vaccine regimen. TRIAL REGISTRATION NCT02416453, NCT02564523, NCT02509494. ClinicalTrials.gov.
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Affiliation(s)
- Houreratou Barry
- Centre MURAZ, Institut National de Santé Publique Bobo-Dioulasso, Burkina Faso
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219; Inria SISTM team, Bordeaux, France
| | - Edouard Lhomme
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219; Inria SISTM team, Bordeaux, France
- CHU Bordeaux, Department of Medical Information, Bordeaux, France
- Vaccine Research Institute (VRI), Créteil, France
| | - Mathieu Surénaud
- Vaccine Research Institute (VRI), Créteil, France
- Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Créteil, France
| | - Moumini Nouctara
- Centre MURAZ, Institut National de Santé Publique Bobo-Dioulasso, Burkina Faso
| | | | - Viki Bockstal
- Janssen Vaccines & Prevention B.V., Leiden, Netherlands
| | - Innocent Valea
- Centre MURAZ, Institut National de Santé Publique Bobo-Dioulasso, Burkina Faso
- Institut de Recherche en Sciences de la Santé/Unité de Recherche Clinique de Nanoro, Burkina Faso
| | - Serge Somda
- Centre MURAZ, Institut National de Santé Publique Bobo-Dioulasso, Burkina Faso
- Université Nazi BONI, UFR Sciences Exactes et Appliquées, Bobo-Dioulasso, Burkina Faso
| | - Halidou Tinto
- Centre MURAZ, Institut National de Santé Publique Bobo-Dioulasso, Burkina Faso
- Institut de Recherche en Sciences de la Santé/Unité de Recherche Clinique de Nanoro, Burkina Faso
| | - Nicolas Meda
- Centre MURAZ, Institut National de Santé Publique Bobo-Dioulasso, Burkina Faso
- UFR Sciences de la santé, Université joseph Ki Zerbo, Ouagadougou, Burkina Faso
| | - Brian Greenwood
- London School of Hygiene & Tropical Medicine (LSHTM), London, United Kingdom
| | - Rodolphe Thiébaut
- Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219; Inria SISTM team, Bordeaux, France
- CHU Bordeaux, Department of Medical Information, Bordeaux, France
- Vaccine Research Institute (VRI), Créteil, France
| | - Christine Lacabaratz
- Vaccine Research Institute (VRI), Créteil, France
- Université Paris-Est Créteil, Faculté de Médecine, INSERM U955, Team 16, Créteil, France
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Munjoma PT, Chandiwana P, Wyss J, Mazhandu AJ, Jordi SBU, Gutsire R, Katsidzira L, Yilmaz B, Misselwitz B, Duri K. Immune activation and inflammation in lactating women on combination antiretroviral therapy: role of gut dysfunction and gut microbiota imbalance. Front Immunol 2023; 14:1280262. [PMID: 38045684 PMCID: PMC10693333 DOI: 10.3389/fimmu.2023.1280262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 10/17/2023] [Indexed: 12/05/2023] Open
Abstract
Introduction Combination antiretroviral therapy (cART) effectively controls HIV; however, chronic low-level viremia and gut microbiota dysbiosis remain significant drivers of gut and systemic inflammation. In this study, we explored the relationship between gut microbiota composition, intestinal inflammation, microbial translocation, and systemic inflammation in women on cART in Sub-Saharan Africa. Methods We conducted a study in HIV-infected and HIV-uninfected lactating women followed up at 6 weeks and 6 months postpartum in Harare, Zimbabwe. We used 16S ribosomal Ribonucleic Acid (rRNA) sequencing and MesoScale Discovery V-Plex assays to examine the gut microbiome and to quantify plasma inflammatory biomarkers, respectively. In addition, we measured fecal calprotectin, plasma lipopolysaccharide-binding protein (LBP), and soluble cluster of differentiation 14 (sCD14) by enzyme-linked immunosorbent assay to assess gut inflammation, microbial translocation, and monocyte/macrophage activation. Results A group of 77 lactating women were studied, of which 35% were HIV-infected. Fecal calprotectin levels were similar by HIV status at both follow-up time points. In the HIV-infected group at 6 weeks postpartum, fecal calprotectin was elevated: median (interquartile range) [158.1 µg/g (75.3-230.2)] in women who had CD4+ T-lymphocyte counts <350 cells/µL compared with those with ≥350 cells/µL [21.1 µg/g (0-58.4)], p = 0.032. Plasma sCD14 levels were significantly higher in the HIV-infected group at both 6 weeks and 6 months postpartum, p < 0.001. Plasma LBP levels were similar, but higher levels were observed in HIV-infected women with elevated fecal calprotectin. We found significant correlations between fecal calprotectin, LBP, and sCD14 with proinflammatory cytokines. Gut microbial alpha diversity was not affected by HIV status and was not affected by use of antibiotic prophylaxis. HIV significantly affected microbial beta diversity, and significant differences in microbial composition were noted. The genera Slackia and Collinsella were relatively more abundant in the HIV-infected group, whereas a lower relative abundance of Clostriduim sensu_stricto_1 was observed. Our study also found correlations between gut microbial taxa abundance and systemic inflammatory biomarkers. Discussion and conclusion HIV-infected lactating women had increased immune activation and increased microbial translocation associated with increased gut inflammation. We identified correlations between the gut inflammation and microbial composition, microbial translocation, and systemic inflammation. The interplay of these parameters might affect the health of this vulnerable population.
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Affiliation(s)
- Privilege Tendai Munjoma
- Immunology Unit, Department of Laboratory Diagnostic and Investigative Sciences, University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS), Harare, Zimbabwe
| | - Panashe Chandiwana
- Immunology Unit, Department of Laboratory Diagnostic and Investigative Sciences, University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS), Harare, Zimbabwe
| | - Jacqueline Wyss
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for Biomedical Research, Maurice Müller Laboratories, University of Bern, Bern, Switzerland
| | - Arthur John Mazhandu
- Immunology Unit, Department of Laboratory Diagnostic and Investigative Sciences, University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS), Harare, Zimbabwe
| | - Sebastian Bruno Ulrich Jordi
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for Biomedical Research, Maurice Müller Laboratories, University of Bern, Bern, Switzerland
| | - Rutendo Gutsire
- Immunology Unit, Department of Laboratory Diagnostic and Investigative Sciences, University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS), Harare, Zimbabwe
| | - Leolin Katsidzira
- Department of Internal Medicine, University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS), Harare, Zimbabwe
| | - Bahtiyar Yilmaz
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for Biomedical Research, Maurice Müller Laboratories, University of Bern, Bern, Switzerland
| | - Benjamin Misselwitz
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department for Biomedical Research, Maurice Müller Laboratories, University of Bern, Bern, Switzerland
| | - Kerina Duri
- Immunology Unit, Department of Laboratory Diagnostic and Investigative Sciences, University of Zimbabwe Faculty of Medicine and Health Sciences (UZ-FMHS), Harare, Zimbabwe
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Planchais C, Molinos-Albert LM, Rosenbaum P, Hieu T, Kanyavuz A, Clermont D, Prazuck T, Lefrou L, Dimitrov JD, Hüe S, Hocqueloux L, Mouquet H. HIV-1 treatment timing shapes the human intestinal memory B-cell repertoire to commensal bacteria. Nat Commun 2023; 14:6326. [PMID: 37816704 PMCID: PMC10564866 DOI: 10.1038/s41467-023-42027-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 09/28/2023] [Indexed: 10/12/2023] Open
Abstract
HIV-1 infection causes severe alterations of gut mucosa, microbiota and immune system, which can be curbed by early antiretroviral therapy. Here, we investigate how treatment timing affects intestinal memory B-cell and plasmablast repertoires of HIV-1-infected humans. We show that only class-switched memory B cells markedly differ between subjects treated during the acute and chronic phases of infection. Intestinal memory B-cell monoclonal antibodies show more prevalent polyreactive and commensal bacteria-reactive clones in late- compared to early-treated individuals. Mirroring this, serum IgA polyreactivity and commensal-reactivity are strongly increased in late-treated individuals and correlate with intestinal permeability and systemic inflammatory markers. Polyreactive blood IgA memory B cells, many of which egressed from the gut, are also substantially enriched in late-treated individuals. Our data establish gut and systemic B-cell polyreactivity to commensal bacteria as hallmarks of chronic HIV-1 infection and suggest that initiating treatment early may limit intestinal B-cell abnormalities compromising HIV-1 humoral response.
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Affiliation(s)
- Cyril Planchais
- Humoral Immunology Unit, Institut Pasteur, Université Paris Cité, INSERM U1222, F-75015, Paris, France
| | - Luis M Molinos-Albert
- Humoral Immunology Unit, Institut Pasteur, Université Paris Cité, INSERM U1222, F-75015, Paris, France
- ISGlobal, Hospital Clínic-Universitat de Barcelona, 08036, Barcelona, Spain
| | - Pierre Rosenbaum
- Humoral Immunology Unit, Institut Pasteur, Université Paris Cité, INSERM U1222, F-75015, Paris, France
| | - Thierry Hieu
- Humoral Immunology Unit, Institut Pasteur, Université Paris Cité, INSERM U1222, F-75015, Paris, France
| | - Alexia Kanyavuz
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006, Paris, France
| | - Dominique Clermont
- Collection of the Institut Pasteur, Institut Pasteur, Université Paris Cité, 75015, Paris, France
| | - Thierry Prazuck
- Service des Maladies Infectieuses et Tropicales, CHR d'Orléans-La Source, 45067, Orléans, France
| | - Laurent Lefrou
- Service d'Hépato-Gastro-Entérologie, CHR d'Orléans-La Source, 45067, Orléans, France
| | - Jordan D Dimitrov
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006, Paris, France
| | - Sophie Hüe
- INSERM U955-Équipe 16, Université Paris-Est Créteil, Faculté de Médecine, 94000, Créteil, France
| | - Laurent Hocqueloux
- Service des Maladies Infectieuses et Tropicales, CHR d'Orléans-La Source, 45067, Orléans, France
| | - Hugo Mouquet
- Humoral Immunology Unit, Institut Pasteur, Université Paris Cité, INSERM U1222, F-75015, Paris, France.
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Govender Y, Morrison CS, Chen PL, Gao X, Yamamoto H, Chipato T, Anderson S, Barbieri R, Salata R, Doncel GF, Fichorova RN. Cervical and systemic innate immunity predictors of HIV risk linked to genital herpes acquisition and time from HSV-2 seroconversion. Sex Transm Infect 2023; 99:311-316. [PMID: 36104248 PMCID: PMC10011014 DOI: 10.1136/sextrans-2022-055458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 08/25/2022] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVES To examine innate immunity predictors of HIV-1 acquisition as biomarkers of HSV-2 risk and biological basis for epidemiologically established HIV-1 predisposition in HSV-2 infected women. METHODS We analysed longitudinal samples from HIV-1 negative visits of 1019 women before and after HSV-2 acquisition. We measured cervical and serum biomarkers of inflammation and immune activation previously linked to HIV-1 risk. Protein levels were Box-Cox transformed and ORs for HSV-2 acquisition were calculated based on top quartile or below/above median levels for all HSV-2 negative visits. Bivariate analysis determined the likelihood of HSV-2 acquisition by biomarker levels preceding infection. Linear mixed-effects models evaluated if biomarkers differed by HSV-2 status defined as negative, incident or established infections with an established infection cut-off starting at 6 months. RESULTS In the cervical compartment, two biomarkers of HIV-1 risk (low SLPI and high BD-2) also predicted HSV-2 acquisition. In addition, HSV-2 acquisition was associated with IL-1β, IL-6, IL-8, MIP-3α, ICAM-1 and VEGF when below median levels. Systemic immunity predictors of HSV-2 acquisition were high sCD14 and IL-6, with highest odds when concomitantly increased (OR=2.23, 1.49-3.35). Concomitant systemic and mucosal predictors of HSV-2 acquisition risk included (1) serum top quartile sCD14 with cervical low SLPI, VEGF and ICAM-1, or high BD-2; (2) serum high IL-6 with cervical low VEGF and ICAM-1, SLPI, IL-1β and IL-6; and (3) serum low C reactive protein with cervical high BD-2 (the only combination also predictive of HIV-1 acquisition). Most cervical biomarkers were decreased after HSV-2 acquisition compared with the HSV-2 negative visits, with incident infections associated with a larger number of suppressed cervical biomarkers and lower serum IL-6 levels compared with established infections. CONCLUSIONS A combination of systemic immunoinflammatory and cervical immunosuppressed states predicts HSV-2 acquisition. A persistently suppressed innate immunity during incident HSV-2 infection may add to the increased HIV-1 susceptibility.
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Affiliation(s)
- Yashini Govender
- Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Charles S Morrison
- Global Health and Population Research, FHI 360, Durham, North Carolina, USA
| | - Pai-Lien Chen
- Global Health and Population Research, FHI 360, Durham, North Carolina, USA
| | - Xiaoming Gao
- Global Health and Population Research, FHI 360, Durham, North Carolina, USA
| | - Hidemi Yamamoto
- Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Tsungai Chipato
- Obstetrics and Gynecology, University of Zimbabwe, Harare, Zimbabwe
| | - Sharon Anderson
- Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia, USA
| | - Robert Barbieri
- Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Robert Salata
- Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Gustavo F Doncel
- Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, Virginia, USA
- CONRAD, Arlington, Virginia, USA
| | - Raina Nakova Fichorova
- Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
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Haddaji A, Ouladlahsen A, Lkhider M, Bensghir R, Jebbar S, Hilmi S, Abbadi I, Sodqi M, Marih L, Pineau P, El Filali KM, Ezzikouri S. Impact of the first-line antiretroviral therapy on soluble markers of inflammation in cohort of human immunodeficiency virus type 1 in Moroccan patients: a prospective study. Arch Microbiol 2023; 205:223. [PMID: 37154966 DOI: 10.1007/s00203-023-03574-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 04/04/2023] [Accepted: 05/01/2023] [Indexed: 05/10/2023]
Abstract
Chronic inflammation and immune activation are a hallmark of HIV-1 infection. In this study, we assessed inflammation biomarkers in a cohort of people living with HIV-1 (PLWH) before and after long-term suppressive combined antiretroviral therapy (cART). A single-center prospective cohort study was conducted to assess inflammatory biomarkers in 86 cART-naive PLWH and after receiving suppressive cART and 50 uninfected controls. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and soluble CD14 (sCD14) were measured using enzyme-linked immunosorbent assay (ELISA). No significant difference was found in IL-6 levels between cART-naïve PLWH and controls (p = 0.753). In contrast, TNF-α level showed a significant difference between cART naïve-PLWH and controls (p = 0.019). Interestingly, IL-6 and TNF-α levels were significantly decreased in PLWH after cART (p < 0.0001). The sCD14 showed no significant difference between cART-naïve patients and controls (p = 0.839) and similar levels were observed in pre- and post-treatment (p = 0.719). Our results highlight the critical importance of early treatment to reduce inflammation and its consequences during HIV infection.
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Affiliation(s)
- Asmaa Haddaji
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, 1, Place Louis Pasteur, 20360, Casablanca, Morocco
- Laboratory of Virology, Oncology, Biosciences, Environment and New Energies, Faculty of Sciences and Techniques of Mohammedia, Hassan II University of Casablanca, Mohammedia, Morocco
| | - Ahd Ouladlahsen
- Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca, Morocco
- Service Des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Mustapha Lkhider
- Laboratory of Virology, Oncology, Biosciences, Environment and New Energies, Faculty of Sciences and Techniques of Mohammedia, Hassan II University of Casablanca, Mohammedia, Morocco
| | - Rajaa Bensghir
- Service Des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Sanaa Jebbar
- Service Des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Soufiane Hilmi
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, 1, Place Louis Pasteur, 20360, Casablanca, Morocco
| | - Islam Abbadi
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, 1, Place Louis Pasteur, 20360, Casablanca, Morocco
- Laboratory of Virology, Oncology, Biosciences, Environment and New Energies, Faculty of Sciences and Techniques of Mohammedia, Hassan II University of Casablanca, Mohammedia, Morocco
| | - Mustapha Sodqi
- Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca, Morocco
- Service Des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Latifa Marih
- Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca, Morocco
- Service Des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Pascal Pineau
- Unité "Organisation Nucléaire et Oncogenèse", INSERM U993, Institut Pasteur, Paris, France
| | - Kamal Marhoum El Filali
- Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, Casablanca, Morocco
- Service Des Maladies Infectieuses, CHU Ibn Rochd, Casablanca, Morocco
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, 1, Place Louis Pasteur, 20360, Casablanca, Morocco.
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ToVinh M, Hörr G, Hoffmeister C, Dobrikova K, Gotter C, Raabe J, Kaiser KM, Ahmad S, Finnemann C, Matejec E, Hack G, Bischoff J, Rieke GJ, Schwarze-Zander C, Boesecke C, van Bremen K, Wasmuth JC, Eis-Hübinger AM, Streeck H, Verhasselt HL, Oldenburg J, Strassburg CP, Rockstroh JK, Spengler U, Krämer B, Nattermann J. HIV-Associated Microbial Translocation May Affect Cytokine Production of CD56bright NK Cells via Stimulation of Monocytes. J Infect Dis 2023; 227:577-582. [PMID: 36520641 DOI: 10.1093/infdis/jiac485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 12/07/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
The mechanisms involved in HIV-associated natural killer (NK) cell impairment are still incompletely understood. We observed HIV infection to be associated with increased plasma levels of IFABP, a marker for gut epithelial barrier dysfunction, and LBP, a marker for microbial translocation. Both IFABP and LBP plasma concentrations were inversely correlated with NK cell interferon-γ production, suggesting microbial translocation to modulate NK cell functions. Accordingly, we found lipopolysaccharide to have an indirect inhibitory effect on NK cells via triggering monocytes' transforming growth factor-β production. Taken together, our data suggest increased microbial translocation to be involved in HIV-associated NK cell dysfunction.
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Affiliation(s)
- Michael ToVinh
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.,German Center for Infection Research, Thematical Translation Units HIV, Cologne/Bonn, Germany
| | - Gregor Hörr
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.,German Center for Infection Research, Thematical Translation Units HIV, Cologne/Bonn, Germany
| | - Christoph Hoffmeister
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.,German Center for Infection Research, Thematical Translation Units HIV, Cologne/Bonn, Germany
| | - Kristiyana Dobrikova
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Christina Gotter
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.,German Center for Infection Research, Thematical Translation Units HIV, Cologne/Bonn, Germany
| | - Jan Raabe
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Kim M Kaiser
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Sarah Ahmad
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Claudia Finnemann
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Eyleen Matejec
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Gudrun Hack
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Jenny Bischoff
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Gereon J Rieke
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Carolynne Schwarze-Zander
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.,German Center for Infection Research, Thematical Translation Units HIV, Cologne/Bonn, Germany
| | - Christoph Boesecke
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.,German Center for Infection Research, Thematical Translation Units HIV, Cologne/Bonn, Germany
| | - Kathrin van Bremen
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.,German Center for Infection Research, Thematical Translation Units HIV, Cologne/Bonn, Germany
| | - Jan-Christian Wasmuth
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.,German Center for Infection Research, Thematical Translation Units HIV, Cologne/Bonn, Germany
| | - Anna M Eis-Hübinger
- Institute of Virology, University Hospital, University of Bonn, Bonn, Germany
| | - Hendrik Streeck
- Institute of Virology, University Hospital, University of Bonn, Bonn, Germany
| | - Hedda L Verhasselt
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Johannes Oldenburg
- Institute for Experimental Hematology and Transfusion Medicine, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.,German Center for Infection Research, Thematical Translation Units HIV, Cologne/Bonn, Germany
| | - Jürgen K Rockstroh
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.,German Center for Infection Research, Thematical Translation Units HIV, Cologne/Bonn, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.,German Center for Infection Research, Thematical Translation Units HIV, Cologne/Bonn, Germany
| | - Benjamin Krämer
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.,German Center for Infection Research, Thematical Translation Units HIV, Cologne/Bonn, Germany
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7
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He J, Shi R, Duan S, Ye R, Yang Y, Wang J, Zu Z, Tang R, Gao J, Liu X, He N. Microbial translocation is associated with advanced liver fibrosis among people with HIV. HIV Med 2022; 23:947-958. [PMID: 35301782 DOI: 10.1111/hiv.13279] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 02/03/2022] [Accepted: 02/08/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND The prevalence of liver complications is increasing among people living with HIV, and microbial translocation (MT) might play a vital role. We conducted a prospective cohort study to evaluate the association between plasma biomarkers of MT and liver fibrosis (LF) among people living with HIV in southwest China. METHOD A total of 665 people living with HIV were enrolled at baseline and had at least one follow-up visit during the 3-year study period. We calculated the Liver Fibrosis Index (FIB-4) to evaluate LF and measured plasma soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP) as surrogate biomarkers for MT. We used ordinal logistic regression to investigate correlates of LF at baseline and used a linear mixed model to examine the association between dynamic changes in MT biomarkers and LF. RESULTS Of the participants, 61 (9.17%) had advanced LF (FIB-4 >3.25), and 193 (29.02%) had moderate LF (1.45 ≤ FIB-4 ≤ 3.25). Patients with advanced LF had higher plasma levels of sCD14 and LBP than those with moderate or no LF, both at baseline and at follow-up. The following factors were significantly associated with advanced LF: the highest quartile of LBP (adjusted odds ratio [aOR] = 1.69; 95% confidence interval [CI] 1.02~2.81), current intravenous drug use (aOR = 1.82; 95% CI 1.06~3.12), baseline CD4 <200 cells/μl (aOR = 3.25; 95% CI 2.13~4.95), hepatitis C virus coinfection (aOR = 2.52; 95% CI 1.41~4.51) and age >50 years (aOR = 32.66; 95% CI 15.89~66.36). LF progression (increasing FIB-4) was significantly associated with increasing sCD14 level (β = 1.11; 95% CI 0.97~1.26; p < 0.001) with covariate adjustment. CONCLUSION The significant relationship between MT and LF may reveal pathogenic mechanisms and potential intervention targets of liver complications among people living with HIV in China.
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Affiliation(s)
- Jiayu He
- Department of Epidemiology, School of Public Health, and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
- Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai, China
| | - Ruizi Shi
- Department of Epidemiology, School of Public Health, and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
- Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai, China
| | - Song Duan
- Dehong Prefecture Center for Disease Control and Prevention, Shanghai, China
| | - Runhua Ye
- Dehong Prefecture Center for Disease Control and Prevention, Shanghai, China
| | - Yuecheng Yang
- Dehong Prefecture Center for Disease Control and Prevention, Shanghai, China
| | - Jibao Wang
- Dehong Prefecture Center for Disease Control and Prevention, Shanghai, China
| | - Zhipeng Zu
- Department of Epidemiology, School of Public Health, and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
- Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai, China
| | - Renhai Tang
- Dehong Prefecture Center for Disease Control and Prevention, Shanghai, China
| | - Jie Gao
- Dehong Prefecture Center for Disease Control and Prevention, Shanghai, China
| | - Xing Liu
- Department of Epidemiology, School of Public Health, and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
| | - Na He
- Department of Epidemiology, School of Public Health, and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
- Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai, China
- Yi-Wu Research Institute, Fudan University, Shanghai, China
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8
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Yonker LM, Gilboa T, Ogata AF, Senussi Y, Lazarovits R, Boribong BP, Bartsch YC, Loiselle M, Rivas MN, Porritt RA, Lima R, Davis JP, Farkas EJ, Burns MD, Young N, Mahajan VS, Hajizadeh S, Lopez XIH, Kreuzer J, Morris R, Martinez EE, Han I, Griswold K, Barry NC, Thompson DB, Church G, Edlow AG, Haas W, Pillai S, Arditi M, Alter G, Walt DR, Fasano A. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier. J Clin Invest 2021; 131:149633. [PMID: 34032635 PMCID: PMC8279585 DOI: 10.1172/jci149633] [Citation(s) in RCA: 177] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 05/19/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUNDWeeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called multisystem inflammatory syndrome in children (MIS-C). Gastrointestinal (GI) symptoms are common in patients with MIS-C, and a severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not been identified to date.METHODSHere, we analyzed biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. Stools were assessed for SARS-CoV-2 by reverse transcription PCR (RT-PCR), and plasma was examined for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As a proof of concept, we treated a patient with MIS-C with larazotide, a zonulin antagonist, and monitored the effect on antigenemia and the patient's clinical response.RESULTSWe showed that in children with MIS-C, a prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The patient with MIS-C treated with larazotide had a coinciding decrease in plasma SARS-CoV-2 spike antigen levels and inflammatory markers and a resultant clinical improvement above that achieved with currently available treatments.CONCLUSIONThese mechanistic data on MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.
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Affiliation(s)
- Lael M. Yonker
- Mucosal Immunology and Biology Research Center and
- Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Tal Gilboa
- Harvard Medical School, Boston, Massachusetts, USA
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA
| | - Alana F. Ogata
- Harvard Medical School, Boston, Massachusetts, USA
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA
| | - Yasmeen Senussi
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Roey Lazarovits
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA
| | - Brittany P. Boribong
- Mucosal Immunology and Biology Research Center and
- Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Yannic C. Bartsch
- Harvard Medical School, Boston, Massachusetts, USA
- Ragon Institute of MIT, MGH and Harvard, Cambridge, Massachusetts, USA
| | | | - Magali Noval Rivas
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Infectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Rebecca A. Porritt
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Infectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Rosiane Lima
- Mucosal Immunology and Biology Research Center and
| | | | | | | | - Nicola Young
- Mucosal Immunology and Biology Research Center and
| | - Vinay S. Mahajan
- Harvard Medical School, Boston, Massachusetts, USA
- Ragon Institute of MIT, MGH and Harvard, Cambridge, Massachusetts, USA
| | - Soroush Hajizadeh
- Harvard Medical School, Boston, Massachusetts, USA
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - Xcanda I. Herrera Lopez
- Harvard Medical School, Boston, Massachusetts, USA
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - Johannes Kreuzer
- Harvard Medical School, Boston, Massachusetts, USA
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - Robert Morris
- Harvard Medical School, Boston, Massachusetts, USA
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - Enid E. Martinez
- Mucosal Immunology and Biology Research Center and
- Harvard Medical School, Boston, Massachusetts, USA
- Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, Massachusetts, USA
| | - Isaac Han
- Harvard Medical School, Boston, Massachusetts, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA
| | - Kettner Griswold
- Harvard Medical School, Boston, Massachusetts, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA
| | - Nicholas C. Barry
- Harvard Medical School, Boston, Massachusetts, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA
| | - David B. Thompson
- Harvard Medical School, Boston, Massachusetts, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA
| | - George Church
- Harvard Medical School, Boston, Massachusetts, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA
- Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
| | - Andrea G. Edlow
- Harvard Medical School, Boston, Massachusetts, USA
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine and
- Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Wilhelm Haas
- Harvard Medical School, Boston, Massachusetts, USA
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - Shiv Pillai
- Harvard Medical School, Boston, Massachusetts, USA
- Ragon Institute of MIT, MGH and Harvard, Cambridge, Massachusetts, USA
| | - Moshe Arditi
- Department of Pediatrics, Division of Infectious Diseases and Immunology, Infectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Galit Alter
- Harvard Medical School, Boston, Massachusetts, USA
- Ragon Institute of MIT, MGH and Harvard, Cambridge, Massachusetts, USA
| | - David R. Walt
- Harvard Medical School, Boston, Massachusetts, USA
- Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA
| | - Alessio Fasano
- Mucosal Immunology and Biology Research Center and
- Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy
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9
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Kazer SW, Walker BD, Shalek AK. Evolution and Diversity of Immune Responses during Acute HIV Infection. Immunity 2021; 53:908-924. [PMID: 33207216 DOI: 10.1016/j.immuni.2020.10.015] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/03/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023]
Abstract
Understanding the earliest immune responses following HIV infection is critical to inform future vaccines and therapeutics. Here, we review recent prospective human studies in at-risk populations that have provided insight into immune responses during acute infection, including additional relevant data from non-human primate (NHP) studies. We discuss the timing, nature, and function of the diverse immune responses induced, the onset of immune dysfunction, and the effects of early anti-retroviral therapy administration. Treatment at onset of viremia mitigates peripheral T and B cell dysfunction, limits seroconversion, and enhances cellular antiviral immunity despite persistence of infection in lymphoid tissues. We highlight pertinent areas for future investigation, and how application of high-throughput technologies, alongside targeted NHP studies, may elucidate immune response features to target in novel preventions and cures.
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Affiliation(s)
- Samuel W Kazer
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Bruce D Walker
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA, USA; HIV Pathogenesis Programme, Nelson R. Mandela School of Medicine, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
| | - Alex K Shalek
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
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10
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Eckard AR, Hughes HY, Hagood NL, O’Riordan MA, Labbato D, Kosco JC, Scott SE, McComsey GA. Fecal Calprotectin Is Elevated in HIV and Related to Systemic Inflammation. J Acquir Immune Defic Syndr 2021; 86:231-239. [PMID: 33065582 PMCID: PMC8285069 DOI: 10.1097/qai.0000000000002538] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 10/05/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Fecal calprotectin (FC), a biomarker of gastrointestinal (GI) inflammation, is used in the diagnosis and management of inflammatory bowel disease. HIV infection severely damages gut-associated lymphoid and epithelial tissues leading to GI inflammation that drives systemic inflammation and increases subsequent risk of comorbidities. For the first time, we compared FC concentrations by HIV and antiretroviral therapy (ART) status and determined the relationship to systemic inflammation. METHODS People with and without HIV were enrolled and underwent a comprehensive clinical and laboratory assessment. Stool samples were collected, and FC was measured by enzyme-linked immunosorbent assay ELISA. Plasma biomarkers of inflammation were also measured. RESULTS One hundred one participants with HIV (83 ART-treated and 18 ART-naive) and 89 uninfected controls were enrolled. There were no significant differences between ART-naive and ART-treated participants, but both HIV groups had significantly higher FC concentrations than controls when FC was considered as a continuous variable or by cut-offs used in inflammatory bowel disease. The highest median and largest proportion of participants with FC >100 µg/g were seen in ART-naive, followed by ART-treated and then controls. Among HIV participants, FC concentrations were positively associated with high-sensitivity C-reactive protein, soluble tumor necrosis factor receptor II, and soluble vascular cellular adhesion molecule and inversely associated with CD4 counts. CONCLUSIONS FC concentrations are elevated in HIV regardless of ART status. ART and immune reconstitution seem to reduce FC but not to concentrations seen in uninfected controls. Our results suggest a role for FC as a noninvasive surrogate measurement of GI inflammation and associated systemic inflammation in HIV.
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Affiliation(s)
| | - Heather Y. Hughes
- Medical University of South Carolina, Charleston, SC, USA
- Ralph H. Johnson VA Medical Center, Charleston, SC, USA
| | | | | | - Danielle Labbato
- University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Julia C. Kosco
- University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Sarah E. Scott
- University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Grace A. McComsey
- University Hospitals Cleveland Medical Center, Cleveland, OH, USA
- Case Western Reserve University School of Medicine, Cleveland, OH, USA
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11
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Concomitant Imbalances of Systemic and Mucosal Immunity Increase HIV Acquisition Risk. J Acquir Immune Defic Syndr 2020; 84:85-91. [PMID: 31985699 DOI: 10.1097/qai.0000000000002299] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND We previously reported association of increased cervical RANTES and decreased secretory leukocyte protease inhibitor (SLPI) with higher risk of HIV acquisition in reproductive-age women. We now examine the interaction of concomitantly altered systemic and cervical immunity on such risk. METHODS We measured immune biomarkers in 4390 cervical and 2390 paired serum specimens at quarterly visits in 218 HIV seroconverters and 784 seronegative women. We assessed proinflammatory (IL-1β, IL-6, IL-8, MIP-3α, and RANTES), anti-inflammatory (IL-1RA and SLPI), vascular activation (vascular endothelial growth factor and Intercellular Adhesion Molecule-1) and defensin (BD2) cervical biomarkers and systemic (peripheral blood) C reactive protein (CRP), IL-6, IL-7, and sCD14 as indicators of immune dysregulation. Biomarker levels were Box-Cox transformed and odds ratios for HIV acquisition calculated based on top quartile or higher/lower than median levels for all HIV-negative visits. RESULTS Subsequent HIV acquisition was associated with 5 of 14 individual biomarkers: low systemic CRP [odds ratio (OR) = 1.49, 1.21-1.83] and IL-6 (OR = 1.23, 1.00-1.51), high cervical BD-2 (OR = 1.33, 1.11-1.58) and RANTES (OR = 1.20, 1.01-1.43), and low cervical IL-1RA (OR = 0.65, 0.48-0.86). Low systemic CRP concomitant with altered cervical immunity, especially high BD2, conveyed highest HIV risk (1.63, 1.29-2.05). Additional markers of increased risk emerged when low systemic CRP coincided with: low systemic IL-6 and IL-7 (OR = 1.53, 1.18-1.97); high cervical IL-8 and MIP-3α (OR = 1.40, 1.07-1.83); high cervical IL-1β and IL-6 (OR = 1.43, 1.09-1.86); or low cervical SLPI (OR = 1.36, 1.08-1.71). CONCLUSIONS Changes in both peripheral and mucosal immunity may precede and predispose women to HIV infection. Suppressed systemic immunity (ie, low CRP) alone or in combination with imbalanced cervical innate immunity (high proinflammatory and low anti-inflammatory mediators) indicated increased vulnerability to infection. Understanding these combined effects on HIV susceptibility is essential to preventing new infections.
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12
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Choudhury B, Brown J, Ransy DG, Brophy J, Kakkar F, Bitnun A, Samson L, Read S, Soudeyns H, Vaudry W, Houston S, Hawkes MT. Endothelial activation is associated with intestinal epithelial injury, systemic inflammation and treatment regimen in children living with vertically acquired HIV-1 infection. HIV Med 2020; 22:273-282. [PMID: 33151601 DOI: 10.1111/hiv.13012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 08/17/2020] [Accepted: 10/09/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Premature development of cardiovascular disease in children living with HIV-1 (CLWH) may be associated with compromised gut barrier function, microbial translocation, immune activation, systemic inflammation and endothelial activation. Biomarkers of these pathways may provide insights into pathogenesis of atherosclerotic disease in CLWH. METHODS This was a cross-sectional study of CLWH enrolled in the multicentre Early Pediatric Initiation-Canadian Child Cure Cohort (EPIC4 ) who were on antiretroviral therapy (ART) with undetectable viral load. Plasma biomarkers of intestinal epithelial injury [intestinal fatty acid binding protein-1 (IFABP)], systemic inflammation [tumour necrosis factor (TNF) and interleukin-6 (IL-6)] and endothelial activation [angiopoietin-2 (Ang2), soluble vascular endothelial growth factor-1 (sVEGFR1) and soluble endoglin (sEng)] were quantified by enzyme-linked immunosorbent assay. Correlation and factor analysis of biomarkers were used to examine associations between innate immune pathways. RESULTS Among 90 CLWH, 16% of Ang2, 15% of sVEGFR1 and 23% of sEng levels were elevated relative to healthy historic controls. Pairwise rank correlations between the three markers of endothelial activation were statistically significant (ρ = 0.69, ρ = 0.61 and ρ = 0.65, P < 0.001 for all correlations). An endothelial activation index, derived by factor analysis of the three endothelial biomarkers, was correlated with TNF (ρ = 0.47, P < 0.001), IL-6 (ρ = 0.60, P < 0.001) and intestinal fatty acid binding protein-1 (ρ = 0.67, P < 0.001). Current or past treatment with ritonavir-boosted lopinavir (LPV/r) was associated with endothelial activation (odds ratio = 5.0, 95% CI: 1.7-17, P = 0.0020). CONCLUSIONS Endothelial activation is prevalent in CLWH despite viral suppression with combination ART and is associated with intestinal epithelial injury, systemic inflammation and treatment with LPV/r.
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Affiliation(s)
- B Choudhury
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - J Brown
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - D G Ransy
- Unité d'immunopathologie virale, Centre de recherche du CHU Sainte-Justine, Montréal, QC, Canada
| | - J Brophy
- Division of Infectious Diseases, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.,Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada
| | - F Kakkar
- Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montréal, QC, Canada
| | - A Bitnun
- Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - L Samson
- Division of Infectious Diseases, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
| | - S Read
- Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - H Soudeyns
- Unité d'immunopathologie virale, Centre de recherche du CHU Sainte-Justine, Montréal, QC, Canada.,Department of Microbiology, Infectiology & Immunology, Université de Montréal, Montréal, QC, Canada
| | - W Vaudry
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - S Houston
- Department of Medicine, Division of Infectious Diseases, University of Alberta, Edmonton, AB, Canada.,School of Public Health, University of Alberta, Edmonton, AB, Canada
| | - M T Hawkes
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.,School of Public Health, University of Alberta, Edmonton, AB, Canada.,Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada.,Stollery Science Lab, Edmonton, AB, Canada.,Women and Children's Health Research Institute, Edmonton, AB, Canada
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13
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Iannetta M, Isnard S, Manuzak J, Guillerme JB, Notin M, Bailly K, Andrieu M, Amraoui S, Vimeux L, Figueiredo S, Charmeteau-de Muylder B, Vaton L, Hatton EX, Samri A, Autran B, Thiébaut R, Chaghil N, Glohi D, Charpentier C, Descamps D, Brun-Vézinet F, Matheron S, Cheynier R, Hosmalin A. Conventional Dendritic Cells and Slan + Monocytes During HIV-2 Infection. Front Immunol 2020; 11:1658. [PMID: 32903610 PMCID: PMC7438582 DOI: 10.3389/fimmu.2020.01658] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/22/2020] [Indexed: 12/25/2022] Open
Abstract
HIV-2 infection is characterized by low viremia and slow disease progression as compared to HIV-1 infection. Circulating CD14++CD16+ monocytes were found to accumulate and CD11c+ conventional dendritic cells (cDC) to be depleted in a Portuguese cohort of people living with HIV-2 (PLWHIV-2), compared to blood bank healthy donors (HD). We studied more precisely classical monocytes; CD16+ inflammatory (intermediate, non-classical and slan+ monocytes, known to accumulate during viremic HIV-1 infection); cDC1, important for cross-presentation, and cDC2, both depleted during HIV-1 infection. We analyzed by flow cytometry these PBMC subsets from Paris area residents: 29 asymptomatic, untreated PLWHIV-2 from the IMMUNOVIR-2 study, part of the ANRS-CO5 HIV-2 cohort: 19 long-term non-progressors (LTNP; infection ≥8 years, undetectable viral load, stable CD4 counts≥500/μL; 17 of West-African origin -WA), and 10 non-LTNP (P; progressive infection; 9 WA); and 30 age-and sex-matched controls: 16 blood bank HD with unknown geographical origin, and 10 HD of WA origin (GeoHD). We measured plasma bacterial translocation markers by ELISA. Non-classical monocyte counts were higher in GeoHD than in HD (54 vs. 32 cells/μL, p = 0.0002). Slan+ monocyte counts were twice as high in GeoHD than in HD (WA: 28 vs. 13 cells/μL, p = 0.0002). Thus cell counts were compared only between participants of WA origin. They were similar in LTNP, P and GeoHD, indicating that there were no HIV-2 related differences. cDC counts did not show major differences between the groups. Interestingly, inflammatory monocyte counts correlated with plasma sCD14 and LBP only in PLWHIV-2, especially LTNP, and not in GeoHD. In conclusion, in LTNP PLWHIV-2, inflammatory monocyte counts correlated with LBP or sCD14 plasma levels, indicating a potential innate immune response to subclinical bacterial translocation. As GeoHD had higher inflammatory monocyte counts than HD, our data also show that specific controls are important to refine innate immunity studies.
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Affiliation(s)
- Marco Iannetta
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Stéphane Isnard
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Jennifer Manuzak
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | | | - Mathilde Notin
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Karine Bailly
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Muriel Andrieu
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Sonia Amraoui
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Lene Vimeux
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | | | | | - Laura Vaton
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Etienne X Hatton
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Assia Samri
- Sorbonne Université, Inserm 1135, Centre d'Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France
| | - Brigitte Autran
- Sorbonne Université, Inserm 1135, Centre d'Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France
| | - Rodolphe Thiébaut
- INSERM, Univ. Bordeaux, CIC 1401, UMR 1219, Bordeaux Population Health Research Center, CHU Bordeaux, Bordeaux, France
| | - Nathalie Chaghil
- INSERM, Univ. Bordeaux, CIC 1401, UMR 1219, Bordeaux Population Health Research Center, CHU Bordeaux, Bordeaux, France
| | - David Glohi
- Service des Maladies Infectieuses, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France
| | - Charlotte Charpentier
- Service des Maladies Infectieuses, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France
| | - Diane Descamps
- Service des Maladies Infectieuses, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France
| | | | - Sophie Matheron
- Service des Maladies Infectieuses, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France.,INSERM, UMR 1137, IAME (Infection Antimicrobials Modelling Evolution), Université de Paris, Paris, France
| | - Remi Cheynier
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
| | - Anne Hosmalin
- Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
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Kyosiimire-Lugemwa J, Anywaine Z, Abaasa A, Levin J, Gombe B, Musinguzi K, Kaleebu P, Grosskurth H, Munderi P, Pala P. Effect of Stopping Cotrimoxazole Preventive Therapy on Microbial Translocation and Inflammatory Markers Among Human Immunodeficiency Virus-Infected Ugandan Adults on Antiretroviral Therapy: The COSTOP Trial Immunology Substudy. J Infect Dis 2020; 222:381-390. [PMID: 31714954 PMCID: PMC7336573 DOI: 10.1093/infdis/jiz494] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 10/02/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Cotrimoxazole preventive therapy (CPT) in human immunodeficiency virus (HIV) infection is a World Health Organization-recommended standard of care in resource-limited settings, but the mechanism of CPT's beneficial effects is unclear. The COSTOP trial (ISRCTN44723643) evaluated the noninferiority of discontinuing CPT in stabilized patients on antiretroviral therapy. The COSTOP immunology substudy was conducted on a subset of COSTOP participants randomized to continue CPT (n = 86) or discontinue CPT (placebo, n = 86) as daily treatment for 1 year. METHODS We evaluated whether CPT reduces microbial translocation, indicated by the presence of bacterial lipopolysaccharide (LPS) and LPS control factors such as soluble CD14 (sCD14) and endotoxin core antibody (EndoCAb immunoglobulin M [IgM]) in plasma. Intestinal barrier damage as indicated by plasma intestinal fatty acid binding protein (IFABP), T-cell activation, and the inflammatory markers C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were also evaluated. RESULTS We found no significant change in markers of microbial translocation (LPS, IFABP, sCD14, and T-cell activation), with decreased EndoCAb IgM. There was significant increase in inflammation markers (CRP and IL-6) after stopping CPT compared to those who continued CPT. CONCLUSIONS These results add to the evidence of immunological benefits of CPT among HIV-infected populations in resource-limited settings. However, no evidence of reducing microbial translocation was observed.
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Affiliation(s)
- Jacqueline Kyosiimire-Lugemwa
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda,Correspondence: J. Kyosiimire-Lugemwa, Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, c/o Uganda Virus Research Institute, PO Box 49, Plot 51–59 Nakiwogo Road, Entebbe, Uganda ()
| | - Zacchaeus Anywaine
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Andrew Abaasa
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Jonathan Levin
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda,School of Public Health, University of the Witwatersrand, Johannesburg, South Africa
| | - Ben Gombe
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Kenneth Musinguzi
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Pontiano Kaleebu
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Heiner Grosskurth
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda,Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Paula Munderi
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda,International Association of Providers of AIDS Care, Washington, District of Columbia, USA
| | - Pietro Pala
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
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Jumare J, Akolo C, Ndembi N, Bwala S, Alabi P, Okwuasaba K, Adebiyi R, Umlauf A, Cherner M, Abimiku A, Charurat M, Blattner WA, Royal W. Elevated Plasma Levels of sCD14 and MCP-1 Are Associated With HIV Associated Neurocognitive Disorders Among Antiretroviral-Naive Individuals in Nigeria. J Acquir Immune Defic Syndr 2020; 84:196-202. [PMID: 32084055 PMCID: PMC11637321 DOI: 10.1097/qai.0000000000002320] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Mononuclear cells play key roles in the pathogenesis of HIV-associated neurocognitive disorders (HAND). Limited studies have looked at the association of markers of monocyte activation with HAND in Africa. We examined this association among HIV-1-infected patients in Nigeria. METHOD A total of 190 HIV-infected treatment-naive participants with immune marker data were included in this cross-sectional study. Plasma levels of soluble CD14 (sCD14), soluble CD163, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and neopterin were measured. Demographically adjusted T scores obtained from a 7-domain neuropsychological test battery were generated, and functional status was assessed using activities of daily living questionnaire. Participants were classified as unimpaired, having asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD) in line with the "Frascati" criteria. RESULTS Thirty-two participants (16.8%) had ANI, 14 (7.4%) had MND, whereas none had HAD. In multivariable linear regression analyses, after adjusting for age, gender, education, CD4 count, and viral load, mean levels of sCD14 were higher among those with ANI and MND as compared with the unimpaired (P = 0.033 and 0.023, respectively). Similarly, the mean level of MCP-1 was greater among those with HAND as compared with the unimpaired (P = 0.047). There were also trends for higher levels of sCD163 and TNF-α among females with MND in univariable analyses. CONCLUSIONS Levels of monocyte activation markers correlate with the severity of impairment among individuals with HAND. The mechanisms that underlie these effects and the potential role of gender require further study.
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Affiliation(s)
- Jibreel Jumare
- University of Maryland School of Medicine, Baltimore, United States, MD 21201
| | - Christopher Akolo
- University of Maryland School of Medicine, Baltimore, United States, MD 21201
| | - Nicaise Ndembi
- University of Maryland School of Medicine, Baltimore, United States, MD 21201
- Institute of Human Virology Nigeria, Federal Capital Territory Abuja, Nigeria
| | - Sunday Bwala
- National Hospital Abuja, Federal Capital Territory Abuja, Nigeria
| | - Peter Alabi
- University of Abuja Teaching Hospital, Federal Capital Territory Abuja, Nigeria
| | - Kanayo Okwuasaba
- Institute of Human Virology Nigeria, Federal Capital Territory Abuja, Nigeria
| | - Ruxton Adebiyi
- Institute of Human Virology Nigeria, Federal Capital Territory Abuja, Nigeria
| | - Anya Umlauf
- University of California San Diego, School of Medicine, San Diego, United States, CA 92103
| | - Mariana Cherner
- University of California San Diego, School of Medicine, San Diego, United States, CA 92103
| | - Alash’le Abimiku
- University of Maryland School of Medicine, Baltimore, United States, MD 21201
| | - Man Charurat
- University of Maryland School of Medicine, Baltimore, United States, MD 21201
| | - William A. Blattner
- University of Maryland School of Medicine, Baltimore, United States, MD 21201
| | - Walter Royal
- University of Maryland School of Medicine, Baltimore, United States, MD 21201
- Neuroscience Institute, Morehouse School of Medicine, Atlanta, United States, GA 30310
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16
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Huang L, Deng J, Lang R, Liao G, Jiang W. Enriched LPS Staining within the Germinal Center of a Lymph Node from an HIV-Infected Long-Term Nonprogressor but Not from Progressors. J Immunol Res 2020; 2020:7471380. [PMID: 32455142 PMCID: PMC7225845 DOI: 10.1155/2020/7471380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 03/30/2020] [Indexed: 12/11/2022] Open
Abstract
An increased level of microbial translocation has been observed in HIV-infected individuals. The host response to microbial translocation is compromised in HIV-infected progressors but remains unknown in HIV-infected long-term nonprogressors (LTNPs). To evaluate microbial translocation in HIV, we assessed lipopolysaccharide (LPS) immunohistochemistry staining in lymph nodes. We found enriched bacterial LPS immunohistochemistry staining in the germinal center of a lymph node from an HIV-infected LTNP, evenly distributed from three progressors with impaired germinal center structures and rarely detected from two HIV-negative individuals. The impaired germinal center structures were consistent with collagen deposition in lymph nodes using immunohistochemistry staining. These results suggest greater immune responses against bacterial LPS translocation in LTNPs, which may reveal an important mechanism in controlling microbial translocation and disease progression in HIV LTNPs.
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Affiliation(s)
- Lei Huang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China 100039
| | - Jianning Deng
- Department of Tuberculosis, The Fourth People's Hospital of Nanning, Nanning, Guangxi, China 530023
| | - Ren Lang
- Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China 100020
| | - Guoyang Liao
- Chief of No. 5 Biologicals Department, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kuming, China 650118
| | - Wei Jiang
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, USA 29425
- Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, USA 29425
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Weinberg A, Huo Y, Kacanek D, Patel K, Watts DH, Wara D, Hoffman RM, Klawitter J, Christians U. Brief Report: Markers of Spontaneous Preterm Delivery in Women Living With HIV: Relationship With Protease Inhibitors and Vitamin D. J Acquir Immune Defic Syndr 2019; 82:181-187. [PMID: 31513074 PMCID: PMC6760328 DOI: 10.1097/qai.0000000000002111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Women living with HIV (WLHIV) have increased risk of spontaneous preterm delivery (SPTD). We sought to identify plasma predictors of SPTD and their correlations with factors that increase the risk of SPTD, such as vitamin D deficiency and use of protease inhibitors. DESIGN Plasma was obtained from 103 WLHIV with SPTD (≤35 weeks gestation) and 205 controls with term deliveries (TDs; ≥37 weeds) matched to cases 2:1 by race and gestational age at blood draw. TNFα, IFNγ, IL6, IL8, IL1β, IL18, IL17, granulocyte colony stimulating factor (GCSF), MCP1, IP10, sIL2Rα, sCD14, vascular endothelial factor a, monocyte colony stimulation factor, GROα, MMP9, IL10, TGFβ, sCTLA4, and eicosanoids were compared between cases adjusting for known SPTD risk factors. RESULTS Participants had similar demographic characteristics, but cases had higher plasma HIV RNA, lower CD4 cells, and more advanced HIV disease compared with controls. High sIL2Rα was associated with increased risk of SPTD. High sCD14, GCSF, PGF2α, and 5-HEPE were marginally associated with increased risk of SPTD. Women who initiated protease inhibitors-containing antiretroviral treatment before or during the first trimester had higher levels of GCSF and 5-HEPE compared with women without such exposure before plasma collection. Vitamin D insufficiency was associated with higher inflammatory sCD14 and PGF2α, and lower anti-inflammatory 5-HEPE. CONCLUSIONS The best plasma predictor of SPTD in WLHIV was sIL2Rα, a marker of T-cell activation. Markers of monocyte activation and eicosanoids were marginally increased in WLHIV and SPTD, suggesting that they may also play a role in the pathogenesis of this disorder.
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Affiliation(s)
- Adriana Weinberg
- Department of Pediatrics, Medicine and Pathology, Anschutz Medical Center, University of Colorado Denver, Aurora, CO 80045
| | - Yanling Huo
- Center for Biostatistics in AIDS Research (CBAR), Harvard T.H. Chan School of Public Health, Boston, MA 02115
| | - Deborah Kacanek
- Center for Biostatistics in AIDS Research (CBAR), Harvard T.H. Chan School of Public Health, Boston, MA 02115
| | - Kunjal Patel
- Center for Biostatistics in AIDS Research (CBAR), Harvard T.H. Chan School of Public Health, Boston, MA 02115
| | - D. Heather Watts
- National Institute of Child Health and Human Development, Bethesda, MD
| | | | - Risa M. Hoffman
- University of California San Francisco, San Francisco, CA
- Department of Medicine, Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles. Los Angeles, CA
| | - Jelena Klawitter
- iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
| | - Uwe Christians
- iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045
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18
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D'Souza RR, Gopalan BP, Rajnala N, Phetsouphanh C, Shet A. Increased monocyte activation with age among HIV-infected long term non-progressor children: implications for early treatment initiation. HIV Med 2019; 20:513-522. [PMID: 31131542 DOI: 10.1111/hiv.12751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2019] [Indexed: 11/30/2022]
Abstract
OBJECTIVES The key to newer therapeutic and eradication approaches often lies in understanding slow disease progression in HIV infection. The paediatric population has been poorly studied in this regard. We aimed to describe a cohort of perinatally infected long-term nonprogressor (LTNP) children living with HIV in India and to evaluate the immune biomarkers of disease progression. METHODS LTNPs (ART-naïve, with a CD4 count ≥ 500 cells/μL at age ≥ 7 years) among the cohort of HIV-infected children were identified and monitored longitudinally, and their CD4 T-cell counts and plasma viral loads were measured every 6 months. The plasma monocyte/macrophage activation markers, namely soluble CD14 (sCD14), soluble CD163 (sCD163) and interferon-inducible protein-10 (IP-10) were measured by enzyme-linked immunosorbent assay (ELISA) in LTNPs and progressors. The Mann-Whitney U-test was used to compare the two groups and P values < 0.05 were considered statistically significant. Spearman's rank or Pearson's correlation coefficient (r) was calculated to determine the associations between variables. RESULTS Among 378 children living with HIV-1 surveyed in our cohort, 40 (10.6%) were LTNPs. Longitudinal analysis of the LTNP data showed that both CD4 count and viral load declined significantly with age (P < 0.0001 for both). Plasma sCD14 levels were significantly (P < 0.005) higher in progressors and sCD163 levels were significantly (P < 0.0001) higher in LTNPs. CONCLUSIONS The prevalence of LTNPs in our cohort of perinatally infected children living with HIV was 10.6%. We observed a trend for associations between the increasing sCD163 monocyte/macrophage activation marker levels, declining CD4 counts and the gradual loss of nonprogressor status with age in the LTNPs. These findings underscore the need for early antiretroviral therapy in those children with proven slow disease progression.
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Affiliation(s)
- R R D'Souza
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.,Division of Infectious Diseases, St John's Research Institute, Bangalore, India
| | - B P Gopalan
- Division of Infectious Diseases, St John's Research Institute, Bangalore, India.,The University of Trans-disciplinary Health Sciences and Technology, Bangalore, India
| | - N Rajnala
- Division of Infectious Diseases, St John's Research Institute, Bangalore, India
| | - C Phetsouphanh
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK
| | - A Shet
- International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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19
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Ayyappan P, Harms RZ, Buckner JH, Sarvetnick NE. Coordinated Induction of Antimicrobial Response Factors in Systemic Lupus Erythematosus. Front Immunol 2019; 10:658. [PMID: 31019506 PMCID: PMC6458289 DOI: 10.3389/fimmu.2019.00658] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 03/11/2019] [Indexed: 12/12/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by dysregulated autoantibody production and complement activation leading to multi-organ damage. The disease is associated with increased intestinal permeability. In this study, we tested the hypothesis that SLE subjects have increased systemic exposure to bacteria. Since bacteria induce the expression of antimicrobial response factors (ARFs), we measured the levels of a series of clinically relevant ARFs in the plasma of SLE subjects. We found that levels of sCD14, lysozyme, and CXCL16 were significantly elevated in SLE subjects. A strong positive correlation was also observed between sCD14 and SELENA-SLEDAI score. Interestingly, the ratio of EndoCAb IgM:total IgM was significantly decreased in SLE and this ratio was negatively correlated with sCD14 levels. Although, there were no significant differences in the levels of lipopolysaccharide binding protein (LBP) and fatty acid binding protein 2 (FABP2), we observed significant positive correlations between lysozyme levels and sCD14, LBP, and FABP2. Moreover, galectin-3 levels also positively correlate with lysozyme, sCD14, and LBP. Since our SLE cohort comprised 43.33% males, we were able to identify gender-specific changes in the levels of ARFs. Overall, these changes in the levels and relationships between ARFs link microbial exposure and SLE. Approaches to reduce microbial exposure or to improve barrier function may provide therapeutic strategies for SLE patients.
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Affiliation(s)
- Prathapan Ayyappan
- Department of Surgery-Transplant, University of Nebraska Medical Center, Omaha, NE, United States
| | - Robert Z. Harms
- Department of Surgery-Transplant, University of Nebraska Medical Center, Omaha, NE, United States
| | - Jane H. Buckner
- Translational Research Program, Benaroya Research Institute, Seattle, WA, United States
| | - Nora E. Sarvetnick
- Department of Surgery-Transplant, University of Nebraska Medical Center, Omaha, NE, United States
- Mary and Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE, United States
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20
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Vidyant S, Chatterjee A, Dhole TN. A single-nucleotide polymorphism in TLR4 is linked with the risk of HIV-1 infection. Br J Biomed Sci 2019; 76:59-63. [PMID: 30569830 DOI: 10.1080/09674845.2018.1559486] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
INTRODUCTION Toll-like receptors (TLRs) are pattern recognition receptors that play a role in innate immunity. Mounting evidence shows that single-nucleotide polymorphisms (SNPs) in TLRs link to various infectious diseases, including human immunodeficiency virus (HIV). We hypothesized links between two TLR4 SNPs (rs4986790 leading to Asp299Gly and rs4986791 leading to Thr399Ile) and HIV, to investigate the frequency of TLR4 polymorphism and its role in patients infected with HIV. MATERIALS AND METHODS We recruited 160 HIV-1 seropositive patients, who were further divided on disease severity based on CD4 count (stages I, II and III), and 270 age- and sex matched healthy HIV-1 seronegative individuals. Subjects were genotyped for TLR4 gene polymorphism by polymerase chain reaction restriction fragment length polymorphism. RESULTS The TLR4 Asp299Gly heterozygous genotype (OR=2.160; p=0.004) and the mutant allele G (OR=2.051; p=0.002) was higher in HIV-1 infection than healthy controls and also in stage I (OR=2.559; p=0.034) compared to different clinical stages of infection. There was no link between the Thr399Ile polymorphism and HIV infection. CONCLUSION The TLR4 (Asp299Gly) SNP is a risk factor in HIV-1 disease susceptibility.
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Affiliation(s)
- S Vidyant
- a Department of Microbiology , Sanjay Gandhi Post Graduate Institute of Medical Sciences , Lucknow , India
| | - A Chatterjee
- b Department of Biomedical sciences , Texas Tech University Health Sciences center , El Paso , TX , USA
| | - T N Dhole
- a Department of Microbiology , Sanjay Gandhi Post Graduate Institute of Medical Sciences , Lucknow , India
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21
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Fitzgerald FC, Lhomme E, Harris K, Kenny J, Doyle R, Kityo C, Shaw LP, Abongomera G, Musiime V, Cook A, Brown JR, Brooks A, Owen-Powell E, Gibb DM, Prendergast AJ, Sarah Walker A, Thiebaut R, Klein N. Microbial Translocation Does Not Drive Immune Activation in Ugandan Children Infected With HIV. J Infect Dis 2019; 219:89-100. [PMID: 30107546 PMCID: PMC6284549 DOI: 10.1093/infdis/jiy495] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/10/2018] [Indexed: 12/12/2022] Open
Abstract
Objective Immune activation is associated with morbidity and mortality during human immunodeficiency virus (HIV) infection, despite receipt of antiretroviral therapy (ART). We investigated whether microbial translocation drives immune activation in HIV-infected Ugandan children. Methods Nineteen markers of immune activation and inflammation were measured over 96 weeks in HIV-infected Ugandan children in the CHAPAS-3 Trial and HIV-uninfected age-matched controls. Microbial translocation was assessed using molecular techniques, including next-generation sequencing. Results Of 249 children included, 142 were infected with HIV; of these, 120 were ART naive, with a median age of 2.8 years (interquartile range [IQR], 1.7-4.0 years) and a median baseline CD4+ T-cell percentage of 20% (IQR, 14%-24%), and 22 were ART experienced, with a median age of 6.5 years (IQR, 5.9-9.2 years) and a median baseline CD4+ T-cell percentage of 35% (IQR, 31%-39%). The control group comprised 107 children without HIV infection. The median increase in the CD4+ T-cell percentage was 17 percentage points (IQR, 12-22 percentage points) at week 96 among ART-naive children, and the viral load was <100 copies/mL in 76% of ART-naive children and 91% of ART-experienced children. Immune activation decreased with ART use. Children could be divided on the basis of immune activation markers into the following 3 clusters: in cluster 1, the majority of children were HIV uninfected; cluster 2 comprised a mix of HIV-uninfected children and HIV-infected ART-naive or ART-experienced children; and in cluster 3, the majority were ART naive. Immune activation was low in cluster 1, decreased in cluster 3, and persisted in cluster 2. Blood microbial DNA levels were negative or very low across groups, with no difference between clusters except for Enterobacteriaceae organisms (the level was higher in cluster 1; P < .0001). Conclusion Immune activation decreased with ART use, with marker clustering indicating different activation patterns according to HIV and ART status. Levels of bacterial DNA in blood were low regardless of HIV status, ART status, and immune activation status. Microbial translocation did not drive immune activation in this setting. Clinical Trials Registration ISRCTN69078957.
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Affiliation(s)
| | - Edouard Lhomme
- INSERM, Bordeaux Population Health Research Centre, UMR 1219, University of Bordeaux, ISPED
- Statistics in System Biology and Translational Medicine (SISTM Team), INRIA Research Centre
- Vaccine Research Institute (VRI), Créteil, France
| | - Kathryn Harris
- Microbiology, Virology, and Infection Prevention and Control, Camelia Botnar Laboratories, GOS National Health Service Foundation Trust
| | - Julia Kenny
- Infection, Immunity, and Inflammation Programme
| | - Ronan Doyle
- Microbiology, Virology, and Infection Prevention and Control, Camelia Botnar Laboratories, GOS National Health Service Foundation Trust
| | | | - Liam P Shaw
- Infection, Immunity, and Inflammation Programme
| | | | | | - Adrian Cook
- Medical Research Council Clinical Trials Unit at UCL
| | - Julianne R Brown
- Microbiology, Virology, and Infection Prevention and Control, Camelia Botnar Laboratories, GOS National Health Service Foundation Trust
| | - Anthony Brooks
- University College London (UCL) Genomics, UCL Great Ormond Street (GOS) Institute of Child Health
| | | | - Diana M Gibb
- Medical Research Council Clinical Trials Unit at UCL
| | - Andrew J Prendergast
- Blizard Institute, Queen Mary University of London, London, United Kingdom
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | | | - Rodolphe Thiebaut
- INSERM, Bordeaux Population Health Research Centre, UMR 1219, University of Bordeaux, ISPED
- Statistics in System Biology and Translational Medicine (SISTM Team), INRIA Research Centre
- Vaccine Research Institute (VRI), Créteil, France
| | - Nigel Klein
- Infection, Immunity, and Inflammation Programme
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Shah SV, Manickam C, Ram DR, Reeves RK. Innate Lymphoid Cells in HIV/SIV Infections. Front Immunol 2017; 8:1818. [PMID: 29326704 PMCID: PMC5733347 DOI: 10.3389/fimmu.2017.01818] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 12/04/2017] [Indexed: 12/12/2022] Open
Abstract
Over the past several years, new populations of innate lymphocytes have been described in mice and primates that are critical for mucosal homeostasis, microbial regulation, and immune defense. Generally conserved from mice to humans, innate lymphoid cells (ILC) have been divided primarily into three subpopulations based on phenotypic and functional repertoires: ILC1 bear similarities to natural killer cells; ILC2 have overlapping functions with TH2 cells; and ILC3 that share many functions with TH17/TH22 cells. ILC are specifically enriched at mucosal surfaces and are possibly one of the earliest responders during viral infections besides being involved in the homeostasis of gut-associated lymphoid tissue and maintenance of gut epithelial barrier integrity. Burgeoning evidence also suggests that there is an early and sustained abrogation of ILC function and numbers during HIV and pathogenic SIV infections, most notably ILC3 in the gastrointestinal tract, which leads to disruption of the mucosal barrier and dysregulation of the local immune system. A better understanding of the direct or indirect mechanisms of loss and dysfunction will be critical to immunotherapeutics aimed at restoring these cells. Herein, we review the current literature on ILC with a particular emphasis on ILC3 and their role(s) in mucosal immunology and the significance of disrupting the ILC niche during HIV and SIV infections.
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Affiliation(s)
- Spandan V Shah
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Cordelia Manickam
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Daniel R Ram
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - R Keith Reeves
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
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Modeling aging in HIV infection in nonhuman primates to address an emerging challenge of the post-ART era. Curr Opin Virol 2017; 25:66-75. [PMID: 28803049 DOI: 10.1016/j.coviro.2017.07.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 07/17/2017] [Accepted: 07/18/2017] [Indexed: 12/22/2022]
Abstract
The advent of antiretroviral therapy (ART) has dramatically improved both quality and length of life for subjects infected with human immunodeficiency virus (HIV), delaying or preventing progression to acquired immunodeficiency syndrome (AIDS). However, the virus induces aging-related changes to the immune system which confound treatment. Additionally, the normal physiologic events that occur during aging lead to deficiencies in immunity which not only exacerbate HIV pathogenesis but also trigger a variety of comorbidities. Here, the synergistic linkage between aging and HIV infection is examined in regard to the immunological and pathological mechanisms that drive both senescence and disease progression. The use of NHPs to investigate potential therapeutic strategies to control the deleterious consequences of aging with HIV infection is also reviewed.
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Comparative evaluation of microbial translocation products (LPS, sCD14, IgM Endocab) in HIV-1 infected Indian individuals. Microb Pathog 2017; 111:331-337. [PMID: 28801271 DOI: 10.1016/j.micpath.2017.08.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 07/20/2017] [Accepted: 08/07/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Microbial translocation of lipopolysaccharides (LPS), soluble CD14 (sCD14) and IgM Endocab levels have been reported to be associated with disease progression in HIV-1 infection. In this longitudinal study, plasma levels of different microbially translocated products (LPS, sCD14, Endocab) was investigated in HIV-1 infected Indian Individuals stratified as Rapid (R), Viremic slow (VS), Slow progressors (S) and healthy controls. METHOD Ten healthy and twenty HIV-1 infected individuals were enrolled. Plasma levels of LPS, sCD14, Endocab was examined using commercially available Limulus Amebocyte assay and enzyme-linked immunosorbent assay (ELISA) enzyme linked immunosorbant assay. RESULTS Elevated levels of sCD14, IgM EndoCab and LPS were observed during HIV-1 infection compared to healthy controls. Rapid progressors had higher levels of sCD14, IgM EndoCab, LPS (median% 1553, 3596, 202.2) compared to viremic slow, slow progressors and healthy controls both at baseline and follow up visits. At baseline, LPS correlated positively with IgM Endocab and negatively with sCD14 levels while at follow-up, significant positive correlation was observed between IgM Endocab and sCD14 (IgM EndoCab r = 0.490, p = 0.05; sCD14 r = 0.051, p = 0.830). Plasma levels of sCD14 correlated positively with viral load in rapid, viremic slow and slow progressors while CD + T cell count correlated positively with sCD14 and IgM EndoCab levels in viremic slow and slow progressors. CONCLUSION Our findings indicate that elevated levels of sCD14, IgM EndoCab and LPS in HIV-1 infected individuals are strong predictors of disease progression and could be considered as candidate biomarkers for disease monitoring.
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Sørensen B, Sommerfelt MA, Stjernholm G, Smith PL, Ökvist M, Hovden AO, Hoddevik G, Redfield R, Ustina V, Jelmert Ø, Zeldis J, Dalgleish A. Correlation of Antibody Responses to a Peptide Antigen gp120-C5 501-512/gp41 732-744 with HIV Disease Progression. AIDS Res Hum Retroviruses 2017; 33:558-566. [PMID: 28051320 DOI: 10.1089/aid.2016.0184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Antibodies to the carboxy-terminal constant (C5) region 5 of the HIV-1 envelope glycoprotein gp120 have previously been associated with slow disease progression. This is one of the regions on gp120 that interact with the transmembrane glycoprotein, gp41, anchoring it to the viral and infected cell membrane. This study analyzed humoral responses to a novel heterodimeric peptide construct comprising the C5501-512 region and a compatible region on gp41732-744. Antibody levels to C5501-512/gp41732-744 were associated with slow disease progression in a treatment naive historical longitudinal cohort from Norway (n = 32; p = .00001). Elevated anti-C5501-512/gp41732-744 antibody levels correlated with moderate viral load (VL) (50-10,000 copies/ml) in a cohort, including natural viral suppressors (NVS) in the Unites States (n = 58; p = .002). Analysis of HIV-positive sera from treatment naive patients in Estonia (n = 300) showed an inverse correlation between anti-C5501-512/gp41732-744 antibodies and VL when comparing VL 2,000-10,000 copies/ml with VL >10,000 (p = .050). Further mapping using peptide inhibition of antibody binding revealed that responses to the C5501-506 subdomain correlated with preserved CD4 counts (n = 55; p = .0012) irrespective of VL in this cohort. The C5 region encompassing C5501-506 shows sequence similarity to the shared epitope (SE) of certain HLA-DR associated with immune dysfunction. Partial antigenic cross-reactivity between SE and C5 is indicated by partial inhibition of NVS antibody binding using SE 15-mer peptide (median 65% inhibition), the C5501-506 6-mer peptide (79% inhibition), and binding of rheumatoid arthritis patient sera to both SE and C5 peptide sequences. The potential influence of these observations on HIV-1 pathogenesis remains to be determined.
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Affiliation(s)
| | | | | | - Peter Lawrence Smith
- St. George's, University of London, Institute of Infection and Immunity, London, United Kingdom
| | | | | | - Gunnar Hoddevik
- Department of Virology, The Norwegian Institute of Public Health, Oslo, Norway
| | - Robert Redfield
- Department of Medicine, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Valentina Ustina
- State Reference Laboratory of HIV Diagnostics, West-Tallinn Central Hospital, Estonia
| | | | - Jerome Zeldis
- Celgene Corp./Celgene Global Health, Summit, New Jersey
| | - Angus Dalgleish
- St. George's, University of London, Institute of Infection and Immunity, London, United Kingdom
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MicroRNA miR-126-5p Enhances the Inflammatory Responses of Monocytes to Lipopolysaccharide Stimulation by Suppressing Cylindromatosis in Chronic HIV-1 Infection. J Virol 2017; 91:JVI.02048-16. [PMID: 28250134 DOI: 10.1128/jvi.02048-16] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Accepted: 02/24/2017] [Indexed: 02/02/2023] Open
Abstract
Persistent immune activation during chronic human immunodeficiency virus type 1 (HIV-1) infection facilitates immune dysfunction and thereby fuels disease progression. The translocation of bacterial derivatives into blood and the hyperinflammatory responsiveness of monocytes have been considered important causative factors for persistent immune activation. Whether microRNAs (miRNAs) are involved in regulating monocyte-mediated inflammatory responses during chronic HIV-1 infection remains elusive. In this study, we show that miR-126-5p functions as a positive regulator of monocyte-mediated inflammatory responses. Significantly increased miRNA miR-126-5p and decreased cylindromatosis (CYLD) were observed in primary monocytes from chronic HIV-1 patients. Inhibition of miR-126-5p in monocytes from chronic HIV-1 patients attenuated the responsiveness of these cells to lipopolysaccharide (LPS) stimulation. Gain-of-function assays confirmed that miR-126-5p could downregulate CYLD, which in turn caused an upregulation of phosphorylation of JNK protein (pJNK) and enhanced inflammatory responses of monocytes to LPS stimulation. Overall, miR-126-5p upregulates the responsiveness of monocytes to LPS stimulation in chronic HIV-1 infection, and the suppression of miR-126-5p and the promotion of CYLD expression in primary monocytes may represent a practical immune intervention strategy to contain persistent inflammation in chronic HIV-1 infection.IMPORTANCE Monocyte-mediated hyperinflammatory responses during chronic HIV-1 infection are important causative factors driving AIDS progression; however, the underlying mechanism has not been fully addressed. We demonstrated that miR-126-5p, one of the most upregulated miRNAs during chronic HIV-1 infection, could enhance the inflammatory responses of monocytes to LPS by suppressing the inhibitory protein CYLD and thereby unleashing the expression of pJNK in the LPS/Toll-like receptor 4/mitogen-activated protein kinase pathway. This observation reveals a new mechanism for HIV-1 pathogenesis, which could be targeted by immune intervention.
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Brief Report: Differential Associations of Interleukin 6 and Intestinal Fatty Acid-Binding Protein With Progressive Untreated HIV-1 Infection in Rakai, Uganda. J Acquir Immune Defic Syndr 2016; 72:15-20. [PMID: 26630672 DOI: 10.1097/qai.0000000000000915] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The significance of HIV-associated immune activation and microbial translocation in Sub-Saharan African population remains poorly defined. We assessed biomarkers of inflammation, microbial translocation, and cellular activation and found most factors elevated in Ugandan HIV-1 seroconverters compared with community-matched controls. In contrast to previous findings in Western cohorts, C-reactive protein, neopterin, and intestinal fatty acid binding protein were not elevated. Higher T-cell activation and IL-6 were associated with faster disease progression. Surprisingly, intestinal fatty acid binding protein, indicative of enterocyte turnover, was higher in slow than in fast progressors. These data suggest differential relationships among biomarkers of intestinal barrier integrity and innate immune activation between developed countries and Sub-Saharan Africa.
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Verstrepen BE, Nieuwenhuis IG, Mooij P, Verschoor EJ, Fagrouch ZC, Kondova I, Boonstra A, Koopman G. Role of microbial translocation in soluble CD14 up-regulation in HIV-, but not in HCV-, infected chimpanzees. J Gen Virol 2016; 97:2599-2607. [PMID: 27534537 DOI: 10.1099/jgv.0.000577] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
During human immunodeficiency virus (HIV) infection, soluble CD14 (sCD14) is up-regulated as a consequence of pathological disruption of the gut epithelial barrier, and subsequent increased microbial translocation. Also in hepatitis C virus (HCV)-infected patients with advanced liver fibrosis, increased levels of sCD14 have been reported. Since the liver plays an important role in clearance of translocated bacterial products, hepatic fibrosis may negatively affect clearance and thus contribute to higher sCD14 levels. Chimpanzees (Pan troglodytes) infected with HCV typically show no signs of liver fibrosis. Here, we have tested the hypothesis that increased levels of sCD14 occur in the absence of hepatic fibrosis or microbial translocation in chimpanzees chronically infected with HCV. sCD14 was up-regulated in both HIV/simian immunodeficiency virus (SIV)- and HCV-infected chimpanzees. In HIV/SIV-infected chimpanzees, intestinal fatty acid-binding protein, a marker for gut perturbation, lipopolysaccharide (LPS)-binding-protein and LPS core antibodies, confirm that sCD14 up-regulation was caused by increased microbial translocation. In HCV-infected chimpanzees, no evidence was found for increased microbial translocation despite up-regulation of sCD14. Additionally, the impact of liver fibrosis on microbial translocation was addressed by direct comparison of chimpanzees with a high HCV load and human patients with advanced fibrosis. These data suggest that only in a small minority of HCV patients, hepatic fibrosis corroborates microbial translocation.
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Affiliation(s)
- Babs E Verstrepen
- Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
| | - Ivonne G Nieuwenhuis
- Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
| | - Petra Mooij
- Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
| | - Ernst J Verschoor
- Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
| | - Zahra C Fagrouch
- Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
| | - Ivanela Kondova
- Division of Pathology and Microbiology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, 3015 CE Rotterdam, The Netherlands
| | - Gerrit Koopman
- Department of Virology, Biomedical Primate Research Centre, 2280 GH Rijswijk, The Netherlands
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Munford RS. Endotoxemia-menace, marker, or mistake? J Leukoc Biol 2016; 100:687-698. [PMID: 27418356 DOI: 10.1189/jlb.3ru0316-151r] [Citation(s) in RCA: 144] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 06/27/2016] [Indexed: 01/19/2023] Open
Abstract
Endotoxemia is in its scientific ascendancy. Never has blood-borne, Gram-negative bacterial endotoxin (LPS) been invoked in the pathogenesis of so many diseases-not only as a trigger for septic shock, once its most cited role, but also as a contributor to atherosclerosis, obesity, chronic fatigue, metabolic syndrome, and many other conditions. Finding elevated plasma endotoxin levels has been essential supporting evidence for each of these links, yet the assays used to detect and quantitate endotoxin have important limitations. This article describes several assays for endotoxin in plasma, reviews what they do and do not measure, and discusses why LPS heterogeneity, LPS trafficking pathways, and host LPS inactivation mechanisms should be considered when interpreting endotoxin assay results.
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Affiliation(s)
- Robert S Munford
- Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, USA
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Márquez M, Fernández Gutiérrez del Álamo C, Girón-González JA. Gut epithelial barrier dysfunction in human immunodeficiency virus-hepatitis C virus coinfected patients: Influence on innate and acquired immunity. World J Gastroenterol 2016; 22:1433-1448. [PMID: 26819512 PMCID: PMC4721978 DOI: 10.3748/wjg.v22.i4.1433] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 10/11/2015] [Accepted: 11/13/2015] [Indexed: 02/06/2023] Open
Abstract
Even in cases where viral replication has been controlled by antiretroviral therapy for long periods of time, human immunodeficiency virus (HIV)-infected patients have several non-acquired immunodeficiency syndrome (AIDS) related co-morbidities, including liver disease, cardiovascular disease and neurocognitive decline, which have a clear impact on survival. It has been considered that persistent innate and acquired immune activation contributes to the pathogenesis of these non-AIDS related diseases. Immune activation has been related with several conditions, remarkably with the bacterial translocation related with the intestinal barrier damage by the HIV or by hepatitis C virus (HCV)-related liver cirrhosis. Consequently, increased morbidity and mortality must be expected in HIV-HCV coinfected patients. Disrupted gut barrier lead to an increased passage of microbial products and to an activation of the mucosal immune system and secretion of inflammatory mediators, which in turn might increase barrier dysfunction. In the present review, the intestinal barrier structure, measures of intestinal barrier dysfunction and the modifications of them in HIV monoinfection and in HIV-HCV coinfection will be considered. Both pathogenesis and the consequences for the progression of liver disease secondary to gut microbial fragment leakage and immune activation will be assessed.
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Pre-cART Elevation of CRP and CD4+ T-Cell Immune Activation Associated With HIV Clinical Progression in a Multinational Case-Cohort Study. J Acquir Immune Defic Syndr 2015; 70:163-71. [PMID: 26017661 DOI: 10.1097/qai.0000000000000696] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore, some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. METHODS A case-cohort study (n = 470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings clinical trial (1571 HIV treatment-naive adults who initiated cART; CD4 T-cell count <300 cells/mm; 9 countries) was conducted. A subcohort of 30 participants per country was randomly selected; additional cases were added from the main cohort. Cases [n = 236 (random subcohort 36; main cohort 200)] had clinical progression (incident WHO stage 3/4 event or death) within 96 weeks after cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. RESULTS Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4 T-cell count was 167 cells per cubic millimeter. In multivariate analysis, highest quartile C-reactive protein concentration [adjusted hazard ratio (aHR), 2.53; 95% confidence interval (CI): 1.02 to 6.28] and CD4 T-cell activation (aHR, 5.18; 95% CI: 1.09 to 24.47) were associated with primary outcomes, compared with lowest quartiles. sCD14 had a trend toward association with clinical failure (aHR, 2.24; 95% CI: 0.96 to 5.21). CONCLUSIONS Measuring C-reactive protein and CD4 T-cell activation may identify patients with CD4 T-cell counts <300 cells per cubic millimeter at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART.
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32
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Yang GB. Intestinal tract and acquired immunodeficiency syndrome. Shijie Huaren Xiaohua Zazhi 2015; 23:4304-4316. [DOI: 10.11569/wcjd.v23.i27.4304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The intestinal tract is closely associated with the transmission, disease progression and the prevention and control of acquired immune deficiency syndrome (AIDS). It has been noticed early in AIDS research that a large percent of AIDS patients presented abnormalities in their intestinal tract, such as diarrhea. Now it is known that the intestinal tract has close and complex relationships with AIDS: (1) the intestinal tract is directly involved in the transmission of human immunodeficiency virus-1 (HIV-1); (2) the damage of the intestinal barrier of HIV/AIDS patients directly promotes AIDS disease progression; and (3) most importantly, the intestinal tract is an important target for the treatment and prevention of HIV/AIDS. The author has previously reviewed the progress in understanding the roles of the intestinal tract in HIV-1 infection and the changes of the intestinal tract after HIV-1 infection. In the current review, I discuss the progress in understanding the roles of the damage of the intestinal mucosal immune system in AIDS disease progression, and the potential application value of the restoration of intestinal mucosal immunity in the treatment of AIDS.
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Silva JN, Polesskaya O, Wei HS, Rasheed IYD, Chamberlain JM, Nishimura C, Feng C, Dewhurst S. Chronic central nervous system expression of HIV-1 Tat leads to accelerated rarefaction of neocortical capillaries and loss of red blood cell velocity heterogeneity. Microcirculation 2015; 21:664-76. [PMID: 24813724 DOI: 10.1111/micc.12145] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 05/06/2014] [Indexed: 12/24/2022]
Abstract
OBJECTIVES HIV-1 infection of the CNS is associated with impairment of CBF and neurocognitive function, and accelerated signs of aging. As normal aging is associated with rarefaction of the cerebral vasculature, we set out to examine chronic viral effects on the cerebral vasculature. METHODS DOX-inducible HIV-1 Tat-tg and WT control mice were used. Animals were treated with DOX for three weeks or five to seven months. Cerebral vessel density and capillary segment length were determined from quantitative image analyses of sectioned cortical tissue. In addition, movement of red blood cells in individual capillaries was imaged in vivo using multiphoton microscopy, to determine RBCV and flux. RESULTS Mean RBCV was not different between Tat-tg mice and age-matched WT controls. However, cortical capillaries from Tat-tg mice showed a significant loss of RBCV heterogeneity and increased RBCF that was attributed to a marked decrease in total cortical capillary length (35-40%) compared to WT mice. CONCLUSIONS Cerebrovascular rarefaction is accelerated in HIV-1 Tat-transgenic mice, and this is associated with alterations in red cell blood velocity. These changes may have relevance to the pathogenesis of HIV-associated neurocognitive disorders in an aging HIV-positive population.
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Affiliation(s)
- Jharon N Silva
- Departments of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA
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Ferreira VH, Nazli A, Dizzell SE, Mueller K, Kaushic C. The anti-inflammatory activity of curcumin protects the genital mucosal epithelial barrier from disruption and blocks replication of HIV-1 and HSV-2. PLoS One 2015; 10:e0124903. [PMID: 25856395 PMCID: PMC4391950 DOI: 10.1371/journal.pone.0124903] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 03/16/2015] [Indexed: 12/04/2022] Open
Abstract
Inflammation is a known mechanism that facilitates HIV acquisition and the spread of infection. In this study, we evaluated whether curcumin, a potent and safe anti-inflammatory compound, could be used to abrogate inflammatory processes that facilitate HIV-1 acquisition in the female genital tract (FGT) and contribute to HIV amplification. Primary, human genital epithelial cells (GECs) were pretreated with curcumin and exposed to HIV-1 or HIV glycoprotein 120 (gp120), both of which have been shown to disrupt epithelial tight junction proteins, including ZO-1 and occludin. Pre-treatment with curcumin prevented disruption of the mucosal barrier by maintaining ZO-1 and occludin expression and maintained trans-epithelial electric resistance across the genital epithelium. Curcumin pre-treatment also abrogated the gp120-mediated upregulation of the proinflammatory cytokines tumor necrosis factor-α and interleukin (IL)-6, which mediate barrier disruption, as well as the chemokines IL-8, RANTES and interferon gamma-induced protein-10 (IP-10), which are capable of recruiting HIV target cells to the FGT. GECs treated with curcumin and exposed to the sexually transmitted co-infecting microbes HSV-1, HSV-2 and Neisseria gonorrhoeae were unable to elicit innate inflammatory responses that indirectly induced activation of the HIV promoter and curcumin blocked Toll-like receptor (TLR)-mediated induction of HIV replication in chronically infected T-cells. Finally, curcumin treatment resulted in significantly decreased HIV-1 and HSV-2 replication in chronically infected T-cells and primary GECs, respectively. All together, our results suggest that the use of anti-inflammatory compounds such as curcumin may offer a viable alternative for the prevention and/or control of HIV replication in the FGT.
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Affiliation(s)
- Victor H. Ferreira
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Aisha Nazli
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Sara E. Dizzell
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Kristen Mueller
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
| | - Charu Kaushic
- Department of Pathology & Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
- McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada
- * E-mail:
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Pulliam L. Cognitive consequences of a sustained monocyte type 1 IFN response in HIV-1 infection. Curr HIV Res 2015; 12:77-84. [PMID: 24862334 DOI: 10.2174/1570162x12666140526113544] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 11/18/2013] [Accepted: 11/18/2013] [Indexed: 12/16/2022]
Abstract
With successful antiretroviral therapy, HIV-1-infected subjects can achieve undetectable peripheral viral loads and immune homeostasis. However, in a subset of individuals on therapy, peripheral monocytes have a gene expression profile characteristic of a type 1 interferon α (IFN) response. This type 1 IFN response correlates with a number of pathogenic conditions including neural cell injury and in combination with HCV infection, cognitive impairment. Lessons from the non-human primate models of pathogenic and nonpathogenic SIV suggest that returning the initial IFN spike in acute SIV infection to normal allows the immune system to control infection and return to homeostasis. An IFN "alarm" signature, defined as monocyte activation with overexpression of the type1 IFN genes IFI27 and CD169, would be useful for identifying a subset of subjects with HIV-1 infection that could progress to a number of pathologies associated with immune activation including cognitive dysfunction. This strategy is being actively pursued for autoimmune diseases that are characterized by an IFN signature. Therapies to block the IFN signature are under investigation as a means to reset the immune system and in a subset of HIV-1-infected subjects may be an adjuvant to standard antiviral therapy to return cognitive function.
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Affiliation(s)
- Lynn Pulliam
- Veterans Affairs Medical Center (113A), 4150 Clement St., San Francisco, CA 94121, USA.
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Asokan M, Sachidanandam V, Satish KS, Ranga U. Attenuation of immune activation in an open-label clinical trial for HIV-AIDS using a polyherbal formulation. Virusdisease 2015; 25:302-13. [PMID: 25674597 DOI: 10.1007/s13337-014-0218-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 05/05/2014] [Indexed: 10/25/2022] Open
Abstract
To explain a stable clinical outcome observed in a previous pilot clinical trial using a polyherbal formulation (PHF) for HIV-AIDS, we, in the present study, evaluated the T cell functions from fresh and stored blood samples. In three clinical groups-the anti-retroviral therapy, PHF and control arms-we compared the circulating levels of lipopolysaccharide, LPS-binding protein, soluble CD14, aspartate transaminase (AST) and alanine transaminase (ALT). Additionally, we evaluated the expression of T cell markers and gag-specific immune responses. The PHF treatment significantly reduced the levels of sCD14, AST and ALT. In a cross-sectional analysis at 30 months post-treatment, in comparison to the control group, the PHF arm showed significantly low per-cell expression of PD1, CD95 and HLA-DR. The PHF treatment appears to have attenuated general immune activation and hepatic inflammation in the study participants. Targeting the mediators of immune activation must be pursued as a useful strategy for HIV-AIDS management.
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Affiliation(s)
- Mangaiarkarasi Asokan
- HIV-AIDS Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, 560 064 India
| | - Vijaya Sachidanandam
- Microbiology and Cell Biology Department, Indian Institute of Science, Bangalore, 560 012 India
| | | | - Udaykumar Ranga
- HIV-AIDS Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, 560 064 India
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Fung TC, Artis D, Sonnenberg GF. Anatomical localization of commensal bacteria in immune cell homeostasis and disease. Immunol Rev 2015; 260:35-49. [PMID: 24942680 DOI: 10.1111/imr.12186] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The mammalian gastrointestinal (GI) tract is colonized by trillions of beneficial commensal bacteria that are essential for promoting normal intestinal physiology. While the majority of commensal bacteria are found in the intestinal lumen, many species have also adapted to colonize different anatomical locations in the intestine, including the surface of intestinal epithelial cells (IECs) and the interior of gut-associated lymphoid tissues. These distinct tissue localization patterns permit unique interactions with the mammalian immune system and collectively influence intestinal immune cell homeostasis. Conversely, dysregulated localization of commensal bacteria can lead to inappropriate activation of the immune system and is associated with numerous chronic infectious, inflammatory, and metabolic diseases. Therefore, regulatory mechanisms that control proper anatomical containment of commensal bacteria are essential to maintain tissue homeostasis and limit pathology. In this review, we propose that commensal bacteria associated with the mammalian GI tract can be anatomically defined as (i) luminal, (ii) epithelial-associated, or (iii) lymphoid tissue-resident, and we discuss the role and regulation of these microbial populations in health and disease.
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Affiliation(s)
- Thomas C Fung
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Wang W, Wu F, Cong Z, Liu K, Qin C, Wei Q. The secretion of IL-22 from mucosal NKp44⁺ NK cells is associated with microbial translocation and virus infection in SIV/SHIV-infected Chinese macaques. J Immunol Res 2014; 2014:387950. [PMID: 25759828 PMCID: PMC4352435 DOI: 10.1155/2014/387950] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 07/18/2014] [Accepted: 07/25/2014] [Indexed: 02/08/2023] Open
Abstract
Microbial translocation (MT) causes systemic immune activation in chronic human immunodeficiency virus (HIV) infection. The role of a novel subtype of innate lymphoid cells, the NKp44(+) NK cells, in HIV/simian immunodeficiency virus- (SIV-) induced MT remains unknown. In this study, 12 simian-human immunodeficiency virus- (SHIV-) infected macaques were chosen and split into two groups based on the MT level. Blood and Peripheral lymphoid tissue were sampled for flow cytometric analysis, viral load detection, and interleukin testing. Then, six naive Chinese macaques were used to determine the dynamics of cytokine secretion from mucosal NKp44(+) NK cells in different phases of SIV infection. As a result, the degranulation capacity and IL-22 production of mucosal NKp44(+) NK cells were associated with the MT level in the SHIV-infected macaques. And the number of mucosal NKp44(+) NK cells and IL-22 secretion by these cells were lower in the chronic phase than in the early acute phase of SIV infection. The number of mucosal NKp44(+) NK cells and interleukin-22 (IL-22) secretion by these cells increased before MT occurred. Therefore, we conclude that a decline in IL-22 production from mucosal NKp44(+) NK cells induced by virus infection may be one of the causes of microbial translocation in HIV/SIV infection.
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Affiliation(s)
- Wei Wang
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, No. 5 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Fangxin Wu
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, No. 5 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Zhe Cong
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, No. 5 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Kejian Liu
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, No. 5 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Chuan Qin
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, No. 5 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
| | - Qiang Wei
- Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health, Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medical Center, Peking Union Medical College, No. 5 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China
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Immune activation is associated with increased gut microbial translocation in treatment-naive, HIV-infected children in a resource-limited setting. J Acquir Immune Defic Syndr 2014; 66:16-24. [PMID: 24378729 DOI: 10.1097/qai.0000000000000096] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gut damage resulting in microbial translocation (MT) is considered a major cause of immune activation (IA) in HIV infection, but data in children are limited, particularly in the absence of antiretroviral therapy. METHODS Sixty perinatally HIV-infected, antiretroviral therapy-naive children, aged 2-12 years, were evaluated for plasma levels of lipopolysaccharide, DNA sequences encoding bacterial 16 second ribosomal DNA (16S rDNA) and soluble CD14 concurrently with markers of CD4 and CD8 T-cell IA and immune exhaustion (IE), CD4 counts, and plasma viral load. At study entry, participants were classified into immune categories (ICs): IC1 (CD4% > 25), IC2 (CD4% 15-25), and IC3 (CD4% < 15). Age-matched HIV-uninfected children served as controls. Data were evaluated at study entry and at 12 months. RESULTS Levels of MT, IA, and IE were increased in patients as compared with controls, were highest in patients in IC3 group, and did not change over 12 months. MT products lipopolysaccharide and 16S rDNA correlated with each other and each correlated with plasma viral load, soluble CD14, and T-cell IA and IE. There was a correlation of IA with IE. CD4 counts and percentage were inversely correlated with MT products and underlying CD4 activation. CONCLUSIONS In a natural history cohort of HIV-infected children not on therapy, MT was more pronounced in the most severely immunocompromised patients and was associated with IA. Strategies to reduce MT may help to reduce IA and prevent CD4 depletion.
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Kristoff J, Haret-Richter G, Ma D, Ribeiro RM, Xu C, Cornell E, Stock JL, He T, Mobley AD, Ross S, Trichel A, Wilson C, Tracy R, Landay A, Apetrei C, Pandrea I. Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication. J Clin Invest 2014; 124:2802-6. [PMID: 24837437 DOI: 10.1172/jci75090] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 03/27/2014] [Indexed: 12/31/2022] Open
Abstract
Damage to the intestinal mucosa results in the translocation of microbes from the intestinal lumen into the circulation. Microbial translocation has been proposed to trigger immune activation, inflammation, and coagulopathy, all of which are key factors that drive HIV disease progression and non-HIV comorbidities; however, direct proof of a causal link is still lacking. Here, we have demonstrated that treatment of acutely SIV-infected pigtailed macaques with the drug sevelamer, which binds microbial lipopolysaccharide in the gut, dramatically reduces immune activation and inflammation and slightly reduces viral replication. Furthermore, sevelamer administration reduced coagulation biomarkers, confirming the contribution of microbial translocation in the development of cardiovascular comorbidities in SIV-infected nonhuman primates. Together, our data suggest that early control of microbial translocation may improve the outcome of HIV infection and limit noninfectious comorbidities associated with AIDS.
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Ferreira VH, Kafka JK, Kaushic C. Influence of common mucosal co-factors on HIV infection in the female genital tract. Am J Reprod Immunol 2014; 71:543-54. [PMID: 24617528 DOI: 10.1111/aji.12221] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Accepted: 01/28/2014] [Indexed: 12/14/2022] Open
Abstract
Women constitute almost half of HIV-infected population globally, and the female genital tract (FGT) accounts for approximately 40% of all new HIV infections worldwide. The FGT is composed of upper and lower parts, distinct in their morphological and functional characteristics. Co-factors in the genital microenvironment, such as presence of hormones, semen, and other sexually transmitted infections, can facilitate or deter HIV infection and play a critical role in determining susceptibility to HIV. In this review, we examine some of these co-factors and their potential influence. Presence of physical and chemical barriers such as epithelial tight junctions, mucus, and anti-microbial peptides can actively block and inhibit viral replication, presenting a significant deterrent to HIV. Upon exposure, HIV and other pathogens first encounter the genital epithelium: cells that express a wide repertoire of pattern recognition receptors that can recognize and directly initiate innate immune responses. These and other interactions in the genital tract can lead to direct and indirect inflammation and enhance the number of local target cells, immune activation, and microbial translocation, all of which promote HIV infection and replication. Better understanding of the dynamics of HIV transmission in the female genital tract would be invaluable for improving the design of prophylactic strategies against HIV.
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Affiliation(s)
- Victor H Ferreira
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Michael G. DeGroote Institute of Infectious Diseases Research, McMaster University, Hamilton, ON, Canada
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Pattern of microbial translocation in patients living with HIV-1 from Vietnam, Ethiopia and Sweden. J Int AIDS Soc 2014; 17:18841. [PMID: 24461466 PMCID: PMC3902178 DOI: 10.7448/ias.17.1.18841] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Revised: 11/23/2013] [Accepted: 12/19/2013] [Indexed: 12/11/2022] Open
Abstract
Introduction The role of microbial translocation (MT) in HIV patients living with HIV from low- and middle-income countries (LMICs) is not fully known. The aim of this study is to investigate and compare the patterns of MT in patients from Vietnam, Ethiopia and Sweden. Methods Cross-sectional samples were obtained from treatment-naïve patients living with HIV-1 and healthy controls from Vietnam (n=83; n=46), Ethiopia (n=9492; n=50) and Sweden (n=51; n=19). Longitudinal samples were obtained from a subset of the Vietnamese (n=24) in whom antiretroviral therapy (ART) and tuberculostatics were given. Plasma lipopolysaccharide (LPS), sCD14 and anti-flagellin IgG were determined by the endpoint chromogenic Limulus Amebocyte Assay and enzyme-linked immunosorbent assay. Results All three biomarkers were significantly increased in patients living with HIV-1 from all countries as compared to controls. No differences were found between males and females. Vietnamese and Ethiopian patients had significantly higher levels of anti-flagellin IgG and LPS, as compared to Swedes. ART reduced these levels for the Vietnamese. Vietnamese patients given tuberculostatics at initiation of ART had significantly lower levels of anti-flagellin IgG and higher sCD14. The biomarkers were lower in Vietnamese who did not develop opportunistic infection. Conclusions Higher MT is common in patients living with HIV compared to healthy individuals, and in patients from LMICs compared to patients from a high-income country. Treatment with tuberculostatics decreased MT while higher levels of MT are associated with a poorer clinical outcome.
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Kuri-Cervantes L, de Oca GSM, Avila-Ríos S, Hernández-Juan R, Reyes-Terán G. Activation of NK cells is associated with HIV-1 disease progression. J Leukoc Biol 2014; 96:7-16. [PMID: 24399837 DOI: 10.1189/jlb.0913514] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The main predictor of HIV-1 disease progression is CD8(+) T cell activation, characterized by elevated expression of CD38 and HLA-DR. NK cells are also activated in viremic HIV-1-infected individuals. However, the relationship between NK cell activation and HIV-1 disease progression remains undefined. We characterized NK cell activation and its association with disease progression in treatment of naive HIV-1-infected individuals, who naturally maintained low/undetectable viremia (elite and viremic controllers), compared with progressors and AIDS subjects, and treated individuals. Our results show that CD38 expression on NK cells, predominantly in the cytotoxic CD56(dim)CD16(+) subset, is associated with HIV-1 disease progression (CD4(+) T cell count and pVL), T cell activation (percentage of CD38(+)HLA-DR(+) T cells), sCD14, inflammation, and innate immune activation. Moreover, NK cell activation is increased in HIV-1-infected subjects progressing to AIDS but not in elite and viremic controllers. ART partially reduces the proportion of activated NK cells. Furthermore, our results show that individuals, who naturally control viremia, maintain low levels of innate immune activation similar to those of uninfected controls.
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Affiliation(s)
- Leticia Kuri-Cervantes
- Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
| | - Gonzalo Salgado-Montes de Oca
- Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
| | - Santiago Avila-Ríos
- Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
| | - Ramón Hernández-Juan
- Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
| | - Gustavo Reyes-Terán
- Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
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Abstract
Combination antiretroviral therapy for HIV infection improves immune function and eliminates the risk of AIDS-related complications but does not restore full health. HIV-infected adults have excess risk of cardiovascular, liver, kidney, bone, and neurologic diseases. Many markers of inflammation are elevated in HIV disease and strongly predictive of the risk of morbidity and mortality. A conceptual model has emerged to explain this syndrome of diseases where HIV-mediated destruction of gut mucosa leads to local and systemic inflammation. Translocated microbial products then pass through the liver, contributing to hepatic damage, impaired microbial clearance, and impaired protein synthesis. Chronic activation of monocytes and altered liver protein synthesis subsequently contribute to a hypercoagulable state. The combined effect of systemic inflammation and excess clotting on tissue function leads to end-organ disease. Multiple therapeutic interventions designed to reverse these pathways are now being tested in the clinic. It is likely that knowledge gained on how inflammation affects health in HIV disease could have implications for our understanding of other chronic inflammatory diseases and the biology of aging.
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Fitzgerald F, Harris K, Doyle R, Alber D, Klein N. Short communication: Evidence that microbial translocation occurs in HIV-infected children in the United Kingdom. AIDS Res Hum Retroviruses 2013; 29:1589-93. [PMID: 23972017 DOI: 10.1089/aid.2013.0097] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Microbial translocation (MT) from the gut is implicated in driving immune activation, increasing morbidity and mortality in HIV. We used bacterial 16S rDNA PCR, Sanger sequencing, and high-throughput sequencing to identify microbial DNA in the bloodstream of HIV-infected children in London, United Kingdom. Blood samples were collected from sequential children attending the HIV clinic at Great Ormond Street Hospital, London. DNA extraction, broad range 16S rDNA PCR, and standard Sanger sequencing were carried out. A subset of positive samples was analyzed by high-throughput sequencing (Roche 454 platform). Of 105 samples collected from sequential children, nine were positive using broad range 16S rDNA PCR (8.6%; 95% CI 4.4-16%). From three amplicons, 16S rDNA sequences were identified as Streptococcus, Propionibacterium acnes, and coagulase-negative Staphylococcus. Four positive samples were analyzed by high-throughput sequencing. In the three samples in which organisms were identified by Sanger sequencing, the same species were identified. Further species, in differing proportions, were identified in all four samples. The identified organisms included known gut orders Bifidobacteriaceae, Lactobacillaceae, Bacteroidales, and Clostridiales. In immunocompetent children of equivalent age, no bacterial DNA was detected in blood using this approach. This is the first study to our knowledge using molecular techniques to identify MT in children in the developed world. Our data indicate that 16S rDNA is detectable in 8.6% of HIV-infected children. Levels of DNA were low and from multiple bacterial species. Further studies are needed to ascertain the importance of MT in HIV-infected children.
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Affiliation(s)
- Felicity Fitzgerald
- Paediatrics Department, North Middlesex University Hospital, London, United Kingdom
- Infectious Diseases and Microbiology Unit, Institute of Child Health, University College London, London, United Kingdom
| | - Kathryn Harris
- Microbiology Department, Camelia Botnar Laboratories, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
| | - Ronan Doyle
- Infectious Diseases and Microbiology Unit, Institute of Child Health, University College London, London, United Kingdom
| | - Dagmar Alber
- The ithree Institute, University of Technology Sydney, Sydney, Australia
| | - Nigel Klein
- Infectious Diseases and Microbiology Unit, Institute of Child Health, University College London, London, United Kingdom
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Fantauzzi A, Falasca F, d’Ettorre G, Cavallari EN, Turriziani O, Vullo V, Mezzaroma I. Microbial translocation, residual viremia and immune senescence in the pathogenesis of HIV-1 infection. World J Clin Infect Dis 2013; 3:47-57. [DOI: 10.5495/wjcid.v3.i4.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 09/16/2013] [Accepted: 11/16/2013] [Indexed: 02/06/2023] Open
Abstract
The pathophysiological mechanisms that underlie the progression of human immunodeficiency virus-1 (HIV-1) disease to full-blown AIDS are not well understood. Findings suggest that, during HIV-1 infection, plasma lipopolysaccharide (LPS) levels, which are used as an indicator of microbial translocation (MT), are elevated throughout the acute and chronic phases of HIV-1 disease. The translocation of bacterial products through the damaged gastrointestinal barrier into the systemic circulation has been described as a driver of immune activation. In contrast, comorbidities that are associated with HIV-1 infection have been attributed to chronic inflammation and immune system dysfunction secondary to MT or low-level HIV-1 replication in plasma and cell reservoirs. Moreover, accelerated aging is significantly associated with chronic inflammation, immune activation, and immune senescence. In this review, we aimed to investigate the role of inflammation as a pivotal marker in the pathogenesis of HIV-1 disease. We will discuss the key features of chronic inflammation and immune activation that are observed during the natural course of the disease and those features that are detected in cART-modified infection. The review will focus on the following aspects of HIV-1 infection: (1) MT; (2) the role of residual viremia; and (3) “immune senescence” or “inflammaging.” Many questions remain unanswered about the potential mechanisms that are involved in HIV-1 pathogenesis. Further studies are needed to better investigate the mechanisms that underlie immune activation and their correlation with HIV-1 disease progression.
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Correlation between different methods to measure microbial translocation and its association with immune activation in long-term suppressed HIV-1-infected individuals. J Acquir Immune Defic Syndr 2013; 64:149-53. [PMID: 24047967 DOI: 10.1097/qai.0b013e31829a2f12] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION Microbial translocation (MT) has been proposed as one of the triggering mechanisms of persistent immune activation associated to HIV-1 infection. Our objectives were to determine the correlation between different measurements of MT in suppressed HIV-1-infected individuals and to evaluate its correlation with immune activation. METHODS Eighteen suppressed HIV-1-infected patients with CD4+ T-cell count above 350 cells per cubic millimeter and undetectable plasma viral load, included in antiretroviral treatment intensification clinical trials, were evaluated. Samples obtained at baseline and at established time points during the trials were analyzed. Lipopolysaccharide (LPS), lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14), and bacterial 16S ribosomal DNA (16S rDNA), and markers of immune activation were determined. RESULTS We analyzed 126 plasma samples from the 18 patients. LPS significantly correlated with sCD14 (P < 0.001, r = 0.407) and LBP (P = 0.042, r = 0.260). Also, a significant correlation was found between sCD14 and LBP (P = 0.009, r = 0.325) but not between bacterial 16S rDNA and LPS, sCD14, or LBP (P = 0.346, P = 0.405, and P = 0.644). On the other hand, no significant correlation was found between LPS, sCD14, or LBP and CD4 (P = 0.418, P = 0.619, and P = 0.728) or CD8 T-cell activation (P = 0.352, P = 0.275, and P = 0.124). Bacterial 16S rDNA correlated with activated CD4 T cells (P = 0.005, r = 0.104) but not with activated CD8 T cells (P = 0.171). CONCLUSIONS There is a good correlation in the quantification of LPS, sCD14, and LBP levels, but not with bacterial 16S rDNA, as measurements of MT. We are unable to ensure that MT directly triggers T-cell immune activation at least among these patients with relatively good immune recovery and under treatment intensification.
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Plasma and mucosal HIV viral loads are associated with genital tract inflammation in HIV-infected women. J Acquir Immune Defic Syndr 2013; 63:485-93. [PMID: 23591635 DOI: 10.1097/qai.0b013e3182961cfc] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Systemic and mucosal inflammation may play a role in HIV control. A cross-sectional comparison was conducted among women in the Women's Interagency HIV Study to explore the hypothesis that compared with HIV-uninfected participants, women with HIV, and, in particular, those with high plasma viral load (PVL) have increased levels of mucosal and systemic inflammatory mediators and impaired mucosal endogenous antimicrobial activity. METHODS Nineteen HIV-uninfected, 40 HIV-infected on antiretroviral therapy (ART) with PVL ≤ 2600 copies/mL (low viral load) (HIV-LVL), and 19 HIV-infected on or off ART with PVL >10,000 (high viral load) (HIV-HVL) were evaluated. Immune mediators and viral RNA were quantified in plasma and cervicovaginal lavage (CVL). The CVL antimicrobial activity was also determined. RESULTS Compared to HIV-uninfected participants, HIV-HVL women had higher levels of mucosal but not systemic proinflammatory cytokines and chemokines, higher Nugent scores, and lower Escherichia coli bactericidal activity. In contrast, there were no significant differences between HIV-LVL and HIV-uninfected controls. After adjusting for PVL, HIV genital tract shedding was significantly associated with higher CVL concentrations of IL-6, IL-1β, MIP-1α, and CCL5 (RANTES) and higher plasma concentrations of MIP-1α. High PVL was associated with higher CVL levels of IL-1β and RANTES, as well as with higher Nugent scores, lower E. coli bactericidal activity, smoking, and lower CD4 counts; smoking and CD4 count retained statistical significance in a multivariate model. CONCLUSIONS Further study is needed to determine if the relationship between mucosal inflammation and PVL is causal and to determine if reducing mucosal inflammation is beneficial.
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Nazli A, Kafka JK, Ferreira VH, Anipindi V, Mueller K, Osborne BJ, Dizzell S, Chauvin S, Mian MF, Ouellet M, Tremblay MJ, Mossman KL, Ashkar AA, Kovacs C, Bowdish DME, Snider DP, Kaul R, Kaushic C. HIV-1 gp120 induces TLR2- and TLR4-mediated innate immune activation in human female genital epithelium. THE JOURNAL OF IMMUNOLOGY 2013; 191:4246-58. [PMID: 24043886 DOI: 10.4049/jimmunol.1301482] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Although women constitute half of all HIV-1-infected people worldwide (UNAIDS World AIDS Day Report, 2011), the earliest events in the female reproductive tract (FRT) during heterosexual HIV-1 transmission are poorly understood. Recently, we demonstrated that HIV-1 could directly impair the mucosal epithelial barrier in the FRT. This suggested that the HIV-1 envelope glycoprotein gp120 was being recognized by a membrane receptor on genital epithelial cells, leading to innate immune activation. In this study, we report that pattern-recognition receptors TLR2 and -4 bind to HIV-1 gp120 and trigger proinflammatory cytokine production via activation of NF-κB. The gp120-TLR interaction also required the presence of heparan sulfate (HS). Bead-binding assays showed that gp120 can bind to HS, TLR2, and TLR4, and studies in transfected HEK293 cells demonstrated that HS and TLR2 and -4 were necessary to mediate downstream signaling. Exposure to seminal plasma from HIV-1-infected and uninfected men with gp120 added to it induced a significant proinflammatory cytokine response from genital epithelial cells and disruption of tight junctions, indicating a role for gp120 in mucosal barrier disruption during HIV-1 heterosexual transmission. These studies provide, for the first time to our knowledge, a possible mechanism by which HIV-1 gp120 could directly initiate innate immune activation in the FRT during heterosexual transmission.
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Affiliation(s)
- Aisha Nazli
- McMaster Immunology Research Centre, Michael G. DeGroote Centre for Learning and Discovery, McMaster University, Hamilton, Ontario L8S 4K1, Canada
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