78 results on '"Jenabian, A."'
Search Results
2. COVID-19 vaccine immunogenicity in people with HIV
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Cecilia T. Costiniuk, Joel Singer, Terry Lee, Marc-André Langlois, Corey Arnold, Yannick Galipeau, Judy Needham, Iva Kulic, Mohammad-Ali Jenabian, Ann N. Burchell, Hasina Shamji, Catharine Chambers, Sharon Walmsley, Mario Ostrowski, Colin Kovacs, Darrell H.S. Tan, Marianne Harris, Mark Hull, Zabrina L. Brumme, Hope R. Lapointe, Mark A. Brockman, Shari Margolese, Enrico Mandarino, Suzanne Samarani, Branka Vulesevic, Bertrand Lebouché, Jonathan B. Angel, Jean-Pierre Routy, Curtis L. Cooper, and Aslam H. Anis
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AIDS Vaccines ,Canada ,COVID-19 Vaccines ,SARS-CoV-2 ,Immunology ,COVID-19 ,HIV Infections ,Antibodies ,Immunogenicity, Vaccine ,Infectious Diseases ,Humans ,RNA, Viral ,Immunology and Allergy ,Prospective Studies - Abstract
Many vaccines require higher/additional doses or adjuvants to provide adequate protection for people with HIV (PWH). Our objective was to compare COVID-19 vaccine immunogenicity in PWH to HIV-negative individuals.In a Canadian multi-center prospective, observational cohort of PWH receiving at least two COVID-19 vaccinations, we measured vaccine-induced immunity at 3 and 6 months post 2nd and 1-month post 3rd doses.The primary outcome was the percentage of PWH mounting vaccine-induced immunity [co-positivity for anti-IgG against SARS-CoV2 Spike(S) and receptor-binding domain proteins] 6 months post 2nd dose. Univariable and multivariable logistic regressions were used to compare COVID-19-specific immune responses between groups and within subgroups.Data from 294 PWH and 267 controls were analyzed. Immunogenicity was achieved in over 90% at each time point in both groups. The proportions of participants achieving comparable anti-receptor-binding domain levels were similar between the group at each time point. Anti-S IgG levels were similar by group at month 3 post 2nd dose and 1-month post 3rd dose. A lower proportion of PWH vs. controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose [92% vs. 99%; odds ratio: 0.14 (95% confidence interval: 0.03, 0.80; P = 0.027)]. In multivariable analyses, neither age, immune non-response, multimorbidity, sex, vaccine type, or timing between doses were associated with reduced IgG response.Vaccine-induced IgG was elicited in the vast majority of PWH and was overall similar between groups. A slightly lower proportion of PWH vs. controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose demonstrating the importance of timely boosting in this population.
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- 2022
3. FoxP3+ CD8 T-cells in acute HIV infection and following early antiretroviral therapy initiation
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Alexis Yero, Tao Shi, Jean-Pierre Routy, Cécile Tremblay, Madeleine Durand, Cecilia T. Costiniuk, and Mohammad-Ali Jenabian
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Immunology ,Immunology and Allergy - Abstract
ObjectivesBesides CD4 regulatory T-cells (Tregs), immunosuppressor FoxP3+ CD8 T-cells are emerging as an important subset of Tregs, which contribute to immune dysfunction and disease progression in HIV infection. However, FoxP3+ CD8 T-cell dynamics in acute HIV infection and following early antiretroviral therapy (ART) initiation remain understudied.MethodsSubsets of FoxP3+ CD8 T-cells were characterized both prospectively and cross-sectionally in PBMCs from untreated acute (n=26) and chronic (n=10) HIV-infected individuals, early ART-treated in acute infection (n=10, median of ART initiation: 5.5 months post-infection), ART-treated in chronic infection (n=10), elite controllers (n=18), and HIV-uninfected controls (n=21).ResultsAcute and chronic infection were associated with increased total, effector memory, and terminally differentiated FoxP3+ CD8 T-cells, while early ART normalized only the frequencies of total FoxP3+ CD8 T-cells. We observed an increase in FoxP3+ CD8 T-cell immune activation (HLADR+/CD38+), senescence (CD57+/CD28-), and PD-1 expression during acute and chronic infection, which were not normalized by early ART. FoxP3+ CD8 T-cells in untreated participants expressed higher levels of immunosuppressive LAP(TGF-β1) and CD39 than uninfected controls, whereas early ART did not affect their expression. The expression of gut-homing markers CCR9 and Integrin-β7 by total FoxP3+ CD8 T-cells and CD39+ and LAP(TGF-β1)+ FoxP3+ CD8 T-cells increased in untreated individuals and remained higher than in uninfected controls despite early ART. Elite controllers share most of the FoxP3+ CD8 T-cell characteristics in uninfected individuals.ConclusionsAlthough early ART normalized total FoxP3+ CD8 T-cells frequencies, it did not affect the persistent elevation of the gut-homing potential of CD39+ and LAP(TGF-β1)+ FoxP3+ CD8 T-cell, which may contribute to immune dysfunction.
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- 2022
4. Impact of extended-release niacin on immune activation in HIV-infected immunological non-responders on effective antiretroviral therapy
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Ido P. Kema, Bertrand Lebouché, Tao Shi, Kim Engler, Réjean Thomas, Alexis Yero, Joel Singer, Omar Farnós, Cecilia T. Costiniuk, Marie-Josée Brouillette, Mohammad-Ali Jenabian, Jean-Pierre Routy, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Lifestyle Medicine (LM)
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CD4-Positive T-Lymphocytes ,Vitamin ,HIV Infections ,Inflammation ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,Niacin ,immune activation ,IDO ,chemistry.chemical_compound ,medicine ,Humans ,tryptophan ,Pharmacology (medical) ,Catabolism ,business.industry ,Tryptophan ,HIV ,Immune dysregulation ,immunological non-responders ,kynurenine ,CD4 Lymphocyte Count ,Infectious Diseases ,chemistry ,inflammation ,Immunology ,medicine.symptom ,business ,Kynurenine ,Immune activation - Abstract
Background: Tryptophan (Trp) catabolism into immunosuppressive kynurenine (Kyn) is involved in immune dysregulation during HIV infection. Niacin (vitamin B3) could control the excess of tryptophan depletion and represents a potential strategy to improve immune functions and CD4 count recovery in immunological non-responder HIV-infected individuals on antiretroviral therapy (ART).Methods: In the CTN PT006 phase 2 pilot randomized trial, 20 adults on ART with CD4Results: Thirteen participants completed the study. Treatment was interrupted in 4 patients due to loss of follow-up or personal reasons and 3 patients were discontinued due to comorbidity risks. All participants maintained a VL Conclusions: Although ER-niacin combined with ART was well-tolerated among immune non-responders and decreased plasma lipids, it did not improve systemic inflammation, Kyn/Trp ratio, and CD4 cell recovery. Overall, ER-niacin was not effective to overcome chronic inflammation in PLWH.
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- 2020
5. Impact of Early ARV Initiation on Relative Proportions of Effector and Regulatory CD8 T Cell in Mesenteric Lymph Nodes and Peripheral Blood During Acute SIV Infection of Rhesus Macaques
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Alexis Yero, Omar Farnos, Julien Clain, Ouafa Zghidi-Abouzid, Henintsoa Rabezanahary, Gina Racine, Jérôme Estaquier, and Mohammad-Ali Jenabian
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Immunology ,Simian Acquired Immunodeficiency Syndrome ,virus diseases ,HIV Infections ,CD8-Positive T-Lymphocytes ,Microbiology ,Macaca mulatta ,T-Lymphocytes, Regulatory ,Disease Models, Animal ,Anti-Retroviral Agents ,Virology ,Insect Science ,Animals ,Simian Immunodeficiency Virus ,Lymph Nodes - Abstract
CD8 T cells are key players in the clearance of human immunodeficiency virus (HIV)-infected cells, such that CD8 T-cell dysfunction contributes to viral persistence despite antiretroviral (ARV) therapy. Mesenteric lymph nodes (MLNs) are major sites of gut mucosal immunity. While different CD8 T cell subsets such as CD8 alpha-alpha (CD8αα), CD8 alpha-beta (CD8αβ), CD8 regulatory T cells (Treg), and mucosa-associated invariant T cells (MAIT) are present in the gut and exhibit distinct functions, their dynamics remain poorly understood due to the lack of accessibility to these tissues in humans. We thus assessed CD8 T cells in MLNs versus peripheral blood in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) following early ARV therapy initiation. SIV infection was associated with an increase over time of both CD8αβ and CD8αα T cells in the blood and MLNs, whereas early ARV initiation significantly decreased the frequencies of CD8αα but not CD8αβ T cells in MLNs. A significant decrease in the expression of chemokine receptors CCR6 and CXCR3 by CD8 T cells, which are essential for T-cell trafficking to the inflammatory sites, was observed in chronically SIV-infected RMs. Surprisingly, while MAIT cells are increased in ARV-treated RMs, their frequencies in MLN are extremely low and were not impacted by ARV. The acute infection resulted in an early CD39
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- 2022
6. Pulmonary Immune Dysregulation and Viral Persistence During HIV Infection
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Yulia Alexandrova, Cecilia T. Costiniuk, and Mohammad-Ali Jenabian
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Immunology ,CD8 T-cell dysfunction ,HIV Infections ,Respiratory Mucosa ,Review ,Adaptive Immunity ,HIV reservoir ,T-Lymphocyte Subsets ,Animals ,Humans ,Immunology and Allergy ,alveolar macrophage (AM) ,Immunity, Mucosal ,Lung ,lungs ,pulmonary immunity ,Macrophages ,HIV ,alveolar macrophages ,RC581-607 ,Viral Load ,Immunity, Innate ,Organ Specificity ,Host-Pathogen Interactions ,HIV-1 ,mucosal immunity ,Immunologic diseases. Allergy - Abstract
Despite the success of antiretroviral therapy (ART), people living with HIV continue to suffer from high burdens of respiratory infections, lung cancers and chronic lung disease at a higher rate than the general population. The lung mucosa, a previously neglected HIV reservoir site, is of particular importance in this phenomenon. Because ART does not eliminate the virus, residual levels of HIV that remain in deep tissues lead to chronic immune activation and pulmonary inflammatory pathologies. In turn, continuous pulmonary and systemic inflammation cause immune cell exhaustion and pulmonary immune dysregulation, creating a pro-inflammatory environment ideal for HIV reservoir persistence. Moreover, smoking, gut and lung dysbiosis and co-infections further fuel the vicious cycle of residual viral replication which, in turn, contributes to inflammation and immune cell proliferation, further maintaining the HIV reservoir. Herein, we discuss the recent evidence supporting the notion that the lungs serve as an HIV viral reservoir. We will explore how smoking, changes in the microbiome, and common co-infections seen in PLWH contribute to HIV persistence, pulmonary immune dysregulation, and high rates of infectious and non-infectious lung disease among these individuals.
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- 2022
7. Plasma Levels of C-Type Lectin REG3α and Gut Damage in People With Human Immunodeficiency Virus
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L P Haraoui, P Rochette, E Beauchamp, M E Thériault, P J Maziade, M Duchastel, B Deligne, A Cloutier-Blais, S Massoud, E Sasseville, P Junod, Franck P. Dupuy, M Boissonnault, M Milne, Louise Labrecque, Claude Fortin, Marina B. Klein, S Lavoie, Ido P. Kema, N Z Miaki, Martel-Laferrière, Petronela Ancuta, Nicole F. Bernard, R Pilarski, A Hamel, Jean-Pierre Routy, A de Pokomandy, C Milne, F Asselin, Nikola Kokinov, S Dufresne, Aging Cohort Groups, Rayoun Ramendra, M E Goyer, Marie Munoz, Mohammad-Ali Jenabian, B Lessard, Benoit Trottier, Madeleine Durand, S Vézina, Stéphane Isnard, F Chano, M A Charron, Jan M. Friedman, Cécile Tremblay, Hal-Gagne, Bertrand Lebouché, M Poliquin, D Longpré, F Villielm, M E Turgeon, M Teltscher, Michael S Silverman, J P Kerba, Cecilia T. Costiniuk, J Cox, John Lin, L Charest, S Poulin, Peter L. Lakatos, E Huchet, Brandon Fombuena, Lifestyle Medicine (LM), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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Adult ,Lipopolysaccharides ,Male ,0301 basic medicine ,beta-Glucans ,Anti-HIV Agents ,CD4-CD8 Ratio ,Lipopolysaccharide Receptors ,HIV Infections ,Pancreatitis-Associated Proteins ,Chromosomal translocation ,Inflammation ,Fatty Acid-Binding Proteins ,Major Articles and Brief Reports ,03 medical and health sciences ,0302 clinical medicine ,C-type lectin ,medicine ,Humans ,Immunology and Allergy ,030212 general & internal medicine ,Intestinal Mucosa ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,business.industry ,Interleukins ,Interleukin-8 ,Middle Aged ,Viral Load ,Antimicrobial ,medicine.disease ,Comorbidity ,Epithelium ,3. Good health ,Cross-Sectional Studies ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Bacterial Translocation ,Immunology ,Disease Progression ,HIV-1 ,Female ,medicine.symptom ,business ,Viral load ,Biomarkers ,CD8 - Abstract
BackgroundRegenerating islet-derived protein 3α (REG3α) is an antimicrobial peptide secreted by intestinal Paneth cells. Circulating REG3α has been identified as a gut damage marker in inflammatory bowel diseases. People living with human immunodeficiency virus (PWH) on antiretroviral therapy (ART) present with an abnormal intestinal landscape leading to microbial translocation, persistent inflammation, and development of non-AIDS comorbidities. Herein, we assessed REG3α as a marker of gut damage in PWH.MethodsPlasma from 169 adult PWH, including 30 elite controllers (ECs), and 30 human immunodeficiency virus (HIV)–uninfected controls were assessed. REG3α plasma levels were compared with HIV disease progression, epithelial gut damage, microbial translocation, and immune activation markers.ResultsCross-sectionally, REG3α levels were elevated in untreated and ART-treated PWH compared with controls. ECs also had elevated REG3α levels compared to controls. Longitudinally, REG3α levels increased in PWH without ART and decreased in those who initiated ART. REG3α levels were inversely associated with CD4 T-cell count and CD4:CD8 ratio, while positively correlated with HIV viral load in untreated participants, and with fungal product translocation and inflammatory markers in all PWH.ConclusionsPlasma REG3α levels were elevated in PWH, including ECs. The gut inflammatory marker REG3α may be used to evaluate therapeutic interventions and predict non-AIDS comorbidity risks in PWH.
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- 2020
8. Cannabinoids and inflammation
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Cecilia T Costiniuk and Mohammad-Ali Jenabian
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CD4-Positive T-Lymphocytes ,0301 basic medicine ,Immunology ,Population ,Simian Acquired Immunodeficiency Syndrome ,HIV Infections ,Inflammation ,Lymphocyte proliferation ,Disease ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Systemic inflammation ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Antiretroviral Therapy, Highly Active ,medicine ,Animals ,Humans ,Immunology and Allergy ,Dronabinol ,030212 general & internal medicine ,education ,Randomized Controlled Trials as Topic ,education.field_of_study ,biology ,business.industry ,Simian immunodeficiency virus ,biology.organism_classification ,Macaca mulatta ,030104 developmental biology ,Infectious Diseases ,Simian Immunodeficiency Virus ,Cytokine secretion ,Cannabis ,medicine.symptom ,business - Abstract
Thanks to the success of modern antiretroviral therapy (ART), people living with HIV (PLWH) have life expectancies which approach that of persons in the general population. However, despite the ability of ART to suppress viral replication, PLWH have high levels of chronic systemic inflammation which drives the development of comorbidities such as cardiovascular disease, diabetes and non-AIDS associated malignancies. Historically, cannabis has played an important role in alleviating many symptoms experienced by persons with advanced HIV infection in the pre-ART era and continues to be used by many PLWH in the ART era, though for different reasons. Δ-Tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD) are the phytocannabinoids, which have received most attention for their medicinal properties. Due to their ability to suppress lymphocyte proliferation and inflammatory cytokine production, there is interest in examining their therapeutic potential as immunomodulators. CB2 receptor activation has been shown in vitro to reduce CD4 T-cell infection by CXCR4-tropic HIV and to reduce HIV replication. Studies involving SIV-infected macaques have shown that Δ-THC can reduce morbidity and mortality and has favourable effects on gut mucosal immunity. Furthermore, ΔTHC administration was associated with reduced lymph node fibrosis and diminished levels of SIV proviral DNA in spleens of rhesus macaques compared with placebo-treated macaques. In humans, cannabis use does not induce a reduction in peripheral CD4 T-cell count or loss of HIV virological control in cross-sectional studies. Rather, cannabis use in ART-treated PLWH was associated with decreased levels of T-cell activation, inflammatory monocytes and pro-inflammatory cytokine secretion, all of which are related to HIV disease progression and comorbidities. Randomized clinical trials should provide further insights into the ability of cannabis and cannabinoid-based medicines to attenuate HIV-associated inflammation. In turn, these findings may provide a novel means to reduce morbidity and mortality in PLWH as adjunctive agents to ART.
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- 2019
9. Dynamics and epigenetic signature of regulatory T-cells following antiretroviral therapy initiation in acute HIV infection
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Cecilia T. Costiniuk, Madeleine Durand, Jean-Pierre Routy, Cécile Tremblay, Christos M. Tsoukas, Omar Farnós, Tao Shi, Alexis Yero, and Mohammad-Ali Jenabian
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Male ,Medicine (General) ,Research paper ,Integrin beta Chains ,CCR9 ,HIV Infections ,antiretroviral therapy (ART) ,T-Lymphocytes, Regulatory ,Epigenesis, Genetic ,0302 clinical medicine ,Transforming Growth Factor beta ,TGF-β1 ,Medicine ,Sida ,0303 health sciences ,medicine.diagnostic_test ,biology ,Apyrase ,FOXP3 ,Forkhead Transcription Factors ,General Medicine ,Methylation ,3. Good health ,Regulatory sequence ,Female ,Adult ,Anti-HIV Agents ,chemical and pharmacologic phenomena ,General Biochemistry, Genetics and Molecular Biology ,Flow cytometry ,Receptors, CCR ,03 medical and health sciences ,R5-920 ,Acquired immunodeficiency syndrome (AIDS) ,Antigens, CD ,FoxP3 ,Humans ,Epigenetics ,030304 developmental biology ,CD39 ,business.industry ,regulatory T-cells (Tregs) ,HIV ,DNA Methylation ,medicine.disease ,biology.organism_classification ,Immunology ,business ,030215 immunology - Abstract
Background HIV infection promotes the expansion of immunosuppressive regulatory T-cells (Tregs), contributing to immune dysfunction, tissue fibrosis and disease progression. Early antiretroviral treatment (ART) upon HIV infection improves CD4 count and decreases immune activation. However, Treg dynamics and their epigenetic regulation following early ART initiation remain understudied. Methods Treg subsets were characterized by flow cytometry in 103 individuals, including untreated HIV-infected participants in acute and chronic phases, ART-treated in early infection, elite controllers (ECs), immunological controllers (ICs), and HIV-uninfected controls. The methylation status of six regulatory regions of the foxp3 gene was assessed using MiSeq technology. Findings Total Treg frequency increased overtime during HIV infection, which was normalized in early ART recipients. Tregs in untreated individuals expressed higher levels of activation and immunosuppressive markers (CD39, and LAP(TGF-β1)), which remained unchanged following early ART. Expression of gut migration markers (CCR9, Integrin-β7) by Tregs was elevated during untreated HIV infection, while they declined with the duration of ART but not upon early ART initiation. Notably, gut-homing Tregs expressing LAP(TGF-β1) and CD39 remained higher despite early treatment. Additionally, the increase in LAP(TGF-β1)+ Tregs overtime were consistent with higher demethylation of conserved non-coding sequence (CNS)-1 in the foxp3 gene. Remarkably, LAP(TGF-β1)-expressing Tregs in ECs were significantly higher than in uninfected subjects, while the markers of Treg activation and gut migration were not different. Interpretation Early ART initiation was unable to control the levels of immunosuppressive Treg subsets and their gut migration potential, which could ultimately contribute to gut tissue fibrosis and HIV disease progression. Funding This study was funded by the Canadian Institutes of Health Research (CIHR, grant MOP 142294) and in part by the AIDS and Infectious Diseases Network of the Reseau SIDA et maladies infectieuses du Fonds de recherche du Quebec-Sante (FRQ-S).
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- 2021
10. HIV-Infected Macrophages Are Infected and Killed by the Interferon-Sensitive Rhabdovirus MG1
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Syim Salahuddin, Mohammad-Ali Jenabian, Teslin S. Sandstrom, Sandra C. Côté, Jonathan B. Angel, Oussama Meziane, Nischal Ranganath, Stephanie C. Burke Schinkel, and Cecilia T. Costiniuk
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T cell ,viruses ,Immunology ,Cell ,HIV Infections ,MG1 ,macrophage ,Biology ,Microbiology ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Interferon ,Virology ,Chlorocebus aethiops ,medicine ,Macrophage ,Animals ,Humans ,Vero Cells ,030304 developmental biology ,oncolytic virus ,0303 health sciences ,Cluster of differentiation ,Macrophages ,virus diseases ,HIV ,Interferon-alpha ,interferon ,3. Good health ,Oncolytic virus ,Oncolytic Viruses ,medicine.anatomical_structure ,HEK293 Cells ,Anti-Retroviral Agents ,030220 oncology & carcinogenesis ,Insect Science ,Cancer cell ,HIV-1 ,Pathogenesis and Immunity ,Rhabdoviridae ,medicine.drug - Abstract
Human immunodeficiency virus type 1 (HIV-1) remains a treatable, but incurable, viral infection. The establishment of viral reservoirs containing latently infected cells remains the main obstacle in the search for a cure., The use of unique cell surface markers to target and eradicate HIV-infected cells has been a longstanding objective of HIV-1 cure research. This approach, however, overlooks the possibility that intracellular changes present within HIV-infected cells may serve as valuable therapeutic targets. For example, the identification of dysregulated antiviral signaling in cancer has led to the characterization of oncolytic viruses capable of preferentially killing cancer cells. Since impairment of cellular antiviral machinery has been proposed as a mechanism by which HIV-1 evades immune clearance, we hypothesized that HIV-infected macrophages (an important viral reservoir in vivo) would be preferentially killed by the interferon-sensitive oncolytic Maraba virus MG1. We first showed that HIV-infected monocyte-derived macrophages (MDM) were more susceptible to MG1 infection and killing than HIV-uninfected cells. As MG1 is highly sensitive to type I interferons (IFN-I), we then investigated whether we could identify IFN-I signaling differences between HIV-infected and uninfected MDM and found evidence of impaired IFN-α responsiveness within HIV-infected cells. Finally, to assess whether MG1 could target a relevant, primary cell reservoir of HIV-1, we investigated its effects in alveolar macrophages (AM) obtained from effectively treated individuals living with HIV-1. As observed with in vitro-infected MDM, we found that HIV-infected AM were preferentially eliminated by MG1. In summary, the oncolytic rhabdovirus MG1 appears to preferentially target and kill HIV-infected cells via impairment of antiviral signaling pathways and may therefore provide a novel approach to an HIV-1 cure. IMPORTANCE Human immunodeficiency virus type 1 (HIV-1) remains a treatable, but incurable, viral infection. The establishment of viral reservoirs containing latently infected cells remains the main obstacle in the search for a cure. Cure research has also focused on only one cellular target of HIV-1 (the CD4+ T cell) while largely overlooking others (such as macrophages) that contribute to HIV-1 persistence. In this study, we address these challenges by describing a potential strategy for the eradication of HIV-infected macrophages. Specifically, we show that an engineered rhabdovirus—initially developed as a cancer therapy—is capable of preferential infection and killing of HIV-infected macrophages, possibly via the same altered antiviral signaling seen in cancer cells. As this rhabdovirus is currently being explored in phase I/II clinical trials, there is potential for this approach to be readily adapted for use within the HIV-1 cure field.
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- 2021
11. Antiretroviral therapy-treated HIV-infected adults with coronary artery disease are characterized by a distinctive regulatory T-cell signature
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Carl Chartrand-Lefebvre, Cécile Tremblay, Omar Farnós, Mohammad-Ali Jenabian, Christos M. Tsoukas, Alexis Yero, Tao Shi, Céline Rothan, Cecilia T. Costiniuk, Madeleine Durand, and Mohamed El-Far
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0301 basic medicine ,Adult ,Regulatory T cell ,Immunology ,CCR4 ,chemical and pharmacologic phenomena ,HIV Infections ,Coronary Artery Disease ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,CXCR3 ,Systemic inflammation ,T-Lymphocytes, Regulatory ,Coronary artery disease ,03 medical and health sciences ,0302 clinical medicine ,Immunology and Allergy ,Medicine ,Humans ,030212 general & internal medicine ,business.industry ,Immune dysregulation ,medicine.disease ,Coronary arteries ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,Anti-Retroviral Agents ,medicine.symptom ,business ,CD8 - Abstract
BACKGROUND Despite the success of antiretroviral therapy (ART) to control viral replication, people living with HIV (PWH) have high levels of chronic systemic inflammation and immune dysregulation which drives accelerated co-morbidities including coronary artery disease (CAD). Regulatory T cells (Tregs) and ectonucleotidases CD39/CD73 are known to be athero-protective via their immunosuppressive and anti-inflammatory functions. DESIGN We assessed the dynamics of Treg subsets in ART-treated PWH with or without CAD vs. HIV-uninfected individuals. METHODS Blood specimens were obtained from 142 participants including ART-treated HIV-infected adults with (n = 43) or without CAD (n = 41), as well as HIV-uninfected controls with (n = 31) or without CAD (n = 27). CAD was determined by the presence of atherosclerotic features on computed tomography angiography of the coronary arteries performed on all study participants. Treg subsets frequencies were assessed by flow cytometry. RESULTS Regardless of statin treatment or ART regimen, HIV+CAD+ individuals had the highest total Treg frequencies and increased thymic generation and output of Tregs (Helios/CD31 expression), while athero-protective CD39+/CD73+ Tregs were significantly depleted in this group. Tregs from PWH had higher expression of CCR6/CXCR3 than uninfected individuals regardless of CAD, while in HIV+CAD+ individuals Tregs expressed the highest levels of CCR4, which limits their maintenance. The lowest levels of CD4+ and CD8+ T-cell immune activation has been observed in HIV+CAD+ within study groups. CONCLUSION ART-treated PWH with diagnosed CAD are characterized by profound alterations in populations of anti-inflammatory and athero-protective Treg subsets. These changes may contribute to atherosclerotic plaque formation and progression during chronic HIV infection in the ART era.
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- 2021
12. HIV Infection and Persistence in Pulmonary Mucosal Double Negative T Cells
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Erwin Schurr, Marianna Orlova, Mohammad-Ali Jenabian, Amélie Pagliuzza, Oussama Meziane, Omar Farnós, Yulia Alexandrova, Petronela Ancuta, Elaine Thomson, Cecilia T. Costiniuk, Elie Haddad, Éric A. Cohen, Ron Olivenstein, Tram N. Q. Pham, Nicolas Chomont, and Syim Salahuddin
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CD4-Positive T-Lymphocytes ,Receptors, CCR6 ,Receptors, CXCR3 ,T-Lymphocytes ,Immunology ,Programmed Cell Death 1 Receptor ,HIV persistence ,Spleen ,HIV Infections ,CD8-Positive T-Lymphocytes ,CXCR3 ,Microbiology ,pulmonary mucosal immunity ,03 medical and health sciences ,T-cell immunity ,0302 clinical medicine ,Immune system ,Acquired immunodeficiency syndrome (AIDS) ,Virology ,medicine ,Animals ,Humans ,double negative (DN) T cells ,Lung ,lungs ,030304 developmental biology ,0303 health sciences ,biology ,CD28 ,virus diseases ,medicine.disease ,3. Good health ,Granzyme B ,medicine.anatomical_structure ,Perforin ,Insect Science ,biology.protein ,Pathogenesis and Immunity ,Bronchoalveolar Lavage Fluid ,CD8 ,030215 immunology - Abstract
Reservoirs of HIV during ART are the primary reasons why HIV/AIDS remains an incurable disease. Indeed, HIV remains latent and unreachable by antiretrovirals in cellular and anatomical sanctuaries, preventing its eradication. The lungs have received very little attention compared to other anatomical reservoirs despite being immunological effector sites exhibiting characteristics ideal for HIV persistence. Furthermore, PLWH suffer from a high burden of pulmonary non-opportunistic infections, suggesting impaired pulmonary immunity despite ART. Meanwhile, various immune cell populations have been proposed to be cellular reservoirs in blood, including CD4− CD8− DN T cells, a subset that may originate from CD4 downregulation by HIV proteins. The present study aims to describe DN T cells in human and humanized mice lungs in relation to intrapulmonary HIV burden. The characterization of DN T cells as cellular HIV reservoirs and the lungs as an anatomical HIV reservoir will contribute to the development of targeted HIV eradication strategies., The lungs are relatively unexplored anatomical human immunodeficiency virus (HIV) reservoirs in the antiretroviral therapy (ART) era. Double negative (DN) T cells are a subset of T cells that lack expression of CD4 and CD8 (CD4− CD8−) and may have both regulatory and effector functions during HIV infection. Notably, circulating DN T cells were previously described as cellular HIV reservoirs. Here, we undertook a thorough analysis of pulmonary versus blood DN T cells of people living with HIV (PLWH) under ART. Bronchoalveolar lavage (BAL) fluid and matched peripheral blood were collected from 35 PLWH on ART and 16 uninfected volunteers without respiratory symptoms. Both PLWH and HIV-negative (HIV−) adults displayed higher frequencies of DN T cells in BAL versus blood, and these cells mostly exhibited an effector memory phenotype. In PLWH, pulmonary mucosal DN T cells expressed higher levels of HLA-DR and several cellular markers associated with HIV persistence (CCR6, CXCR3, and PD-1) than blood. We also observed that DN T cells were less senescent (CD28− CD57+) and expressed less immunosuppressive ectonucleotidase (CD73/CD39), granzyme B, and perforin in the BAL fluid than in the blood of PLWH. Importantly, fluorescence-activated cell sorter (FACS)-sorted DN T cells from the BAL fluid of PLWH under suppressive ART harbored HIV DNA. Using the humanized bone marrow-liver-thymus (hu-BLT) mouse model of HIV infection, we observed higher infection frequencies of lung DN T cells than those of the blood and spleen in both early and late HIV infection. Overall, our findings show that HIV is seeded in pulmonary mucosal DN T cells early following infection and persists in these potential cellular HIV reservoirs even during long-term ART. IMPORTANCE Reservoirs of HIV during ART are the primary reasons why HIV/AIDS remains an incurable disease. Indeed, HIV remains latent and unreachable by antiretrovirals in cellular and anatomical sanctuaries, preventing its eradication. The lungs have received very little attention compared to other anatomical reservoirs despite being immunological effector sites exhibiting characteristics ideal for HIV persistence. Furthermore, PLWH suffer from a high burden of pulmonary non-opportunistic infections, suggesting impaired pulmonary immunity despite ART. Meanwhile, various immune cell populations have been proposed to be cellular reservoirs in blood, including CD4− CD8− DN T cells, a subset that may originate from CD4 downregulation by HIV proteins. The present study aims to describe DN T cells in human and humanized mice lungs in relation to intrapulmonary HIV burden. The characterization of DN T cells as cellular HIV reservoirs and the lungs as an anatomical HIV reservoir will contribute to the development of targeted HIV eradication strategies.
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- 2020
13. Peculiar Phenotypic and Cytotoxic Features of Pulmonary Mucosal CD8 T Cells in People Living with HIV Receiving Long-Term Antiretroviral Therapy
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Marianna Orlova, Petronela Ancuta, Elaine Thomson, Cecilia T. Costiniuk, Franck P. Dupuy, Ronald Olivenstein, Nicolas Chomont, Syim Salahuddin, Mohammad-Ali Jenabian, Madeleine Durand, Erwin Schurr, Oussama Meziane, Yulia Alexandrova, Nicole F. Bernard, and Jérôme Estaquier
- Subjects
Adult ,Cytotoxicity, Immunologic ,Male ,Immunology ,Population ,HIV Infections ,Respiratory Mucosa ,Lymphocyte Activation ,Cell Degranulation ,HIV Long-Term Survivors ,Immunophenotyping ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,education ,Cells, Cultured ,Cellular Senescence ,Immune Evasion ,education.field_of_study ,Lung ,medicine.diagnostic_test ,biology ,business.industry ,Degranulation ,Middle Aged ,Granzyme B ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Phenotype ,Perforin ,Anti-Retroviral Agents ,biology.protein ,HIV-1 ,Female ,business ,Immunologic Memory ,030215 immunology ,T-Lymphocytes, Cytotoxic - Abstract
People living with HIV have high burdens of chronic lung disease, lung cancers, and pulmonary infections despite antiretroviral therapy (ART). The rates of tobacco smoking by people living with HIV vastly exceed that of the general population. Furthermore, we showed that HIV can persist within the lung mucosa despite long-term ART. As CD8 T cell cytotoxicity is pivotal for controlling viral infections and eliminating defective cells, we explored the phenotypic and functional features of pulmonary versus peripheral blood CD8 T cells in ART-treated HIV+ and uninfected controls. Bronchoalveolar lavage fluid and matched blood were obtained from asymptomatic ART-treated HIV+ smokers (n = 11) and nonsmokers (n = 15) and uninfected smokers (n = 7) and nonsmokers (n = 10). CD8 T cell subsets and phenotypes were assessed by flow cytometry. Perforin/granzyme B content, degranulation (CD107a expression), and cytotoxicity against autologous Gag peptide-pulsed CD4 T cells (Annexin V+) following in vitro stimulation were assessed. In all groups, pulmonary CD8 T cells were enriched in effector memory subsets compared with blood and displayed higher levels of activation (HLA-DR+) and exhaustion (PD1+) markers. Significant reductions in proportions of senescent pulmonary CD28−CD57+ CD8 T cells were observed only in HIV+ smokers. Pulmonary CD8 T cells showed lower perforin expression ex vivo compared with blood CD8 T cells, with reduced granzyme B expression only in HIV+ nonsmokers. Bronchoalveolar lavage CD8 T cells showed significantly less in vitro degranulation and CD4 killing capacity than blood CD8 T cells. Therefore, pulmonary mucosal CD8 T cells are more differentiated, activated, and exhausted, with reduced killing capacity in vitro than blood CD8 T cells, potentially contributing to a suboptimal anti-HIV immune response within the lungs.
- Published
- 2020
14. Natural and vaccine-induced B cell-derived systemic and mucosal humoral immunity to human papillomavirus
- Author
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Laurent Bélec, Jean-François Meye, Ralph-Sydney Mboumba Bouassa, David Veyer, Hélène Péré, Mohammad-Ali Jenabian, Antoine Touzé, Laboratoire de Virologie [Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), École Doctorale Régionale en Infectiologie Tropicale [Franceville, Gabon], Immunothérapie et traitement anti-angiogénique en cancérologie [Paris], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Paris Descartes - Paris 5 (UPD5), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Université des sciences de la santé, Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
- Subjects
Male ,0301 basic medicine ,Microbiology (medical) ,Human papillomavirus infection ,[SDV]Life Sciences [q-bio] ,030106 microbiology ,Alphapapillomavirus ,CD8-Positive T-Lymphocytes ,Microbiology ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Virology ,medicine ,Animals ,Humans ,Papillomavirus Vaccines ,030212 general & internal medicine ,Neutralizing antibody ,B cell ,biology ,business.industry ,Papillomavirus Infections ,HPV infection ,HPV-associated cancers ,medicine.disease ,Immunity, Humoral ,3. Good health ,Infectious Diseases ,medicine.anatomical_structure ,Antibody Formation ,Immunology ,Humoral immunity ,Virus-like particle HPV prophylactic vaccine ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,biology.protein ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,Antibody ,business ,Natural and vaccine-induced humoral immune responses ,CD8 - Abstract
International audience; Introduction: Human papillomavirus (HPV) are the causative agent of mucosal neoplasia. Both cervical, anal and oropharyngeal cancers incidence is constantly increasing, making the HPV infection, a significant worldwide concern. Together, the CD8+ T cytotoxic cell-mediated response and the HPV-specific antibody response control most of the HPV infections before the development of cancers. Areas covered: We searched the MEDLINE and EMBASE databases and identified 228 eligible studies from 1987 to 2019 which examines both naturally acquired and vaccine induced humoral immunity against HPV infection in female and male subjects from worldwide origin. Herein, we synthesize current knowledge on the features of systemic and mucosal humoral immunity against HPV. We discuss the issues of the balance between the viral clearance or the escape to the host immune response, the differences between natural and vaccine-induced HPV-specific antibodies and their neutralizing capability. We also discuss the protection afforded after natural infection or following prophylactic vaccination. Expert opinion: Understanding the antibody response induced by HPV infection has led to the design of first-generation prophylactic vaccines. Now, prophylactic vaccination induces protective and long-lasting antibody response which would also strengthened the natural moderate humoral response in people previously exposed to the virus.
- Published
- 2020
15. Acute inflammation and pathogenesis of SARS-CoV-2 infection: Cannabidiol as a potential anti-inflammatory treatment?
- Author
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Cecilia T. Costiniuk and Mohammad-Ali Jenabian
- Subjects
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Endocrinology, Diabetes and Metabolism ,Immunology ,Pneumonia, Viral ,Anti-Inflammatory Agents ,Inflammation ,Article ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,Betacoronavirus ,Pandemic ,medicine ,Immunology and Allergy ,Cannabidiol ,Humans ,Pandemics ,biology ,business.industry ,SARS-CoV-2 ,COVID-19 ,biology.organism_classification ,medicine.disease ,Cytokine release syndrome ,Pneumonia ,medicine.symptom ,business ,Coronavirus Infections ,Cytokine Release Syndrome ,medicine.drug - Published
- 2020
16. Plasma Extracellular Vesicle Subtypes May be Useful as Potential Biomarkers of Immune Activation in People With HIV
- Author
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Mohammad-Ali Jenabian, Sylvie Trottier, Wilfried Wenceslas Bazié, Caroline Gilbert, Cécile Tremblay, Michel Alary, Patrick Provost, Julien Boucher, Julien Vitry, Jean-Pierre Routy, and Benjamin Goyer
- Subjects
Microbiology (medical) ,Immunology ,CD4-CD8 Ratio ,Inflammation ,Biology ,Systemic inflammation ,immune activation ,miR-155 ,mir-223 ,CD4/CD8 ratio ,microRNA ,medicine ,Immunology and Allergy ,miR-92 ,Molecular Biology ,biomarkers ,Extracellular vesicle ,miR-223 ,Infectious Diseases ,inflammation ,HIV-1 ,medicine.symptom ,extracellular vesicles ,CD8 ,Research Article - Abstract
Background: Extracellular vesicles (EVs) are intercellular messengers with epigenetic potential since they can shuttle microRNA (miRNA). EVs and miRNA play a role in human immunodeficiency virus (HIV) infection immunopathogenesis. Chronic immune activation and systemic inflammation during HIV infection despite effective antiretroviral therapy (ART) are associated with non-acquired immunodeficiency syndrome (AIDS) comorbidities in people living with HIV (PLWH). Analysis of plasma EVs and their miRNA content may be useful as immune activation or inflammatory biomarkers in PLWH receiving ART. In this study, we hypothesized that the number, size, and miRNA of large and small EVs could reflect immune activation associated with an elevated CD8 T-cell count or a low CD4/CD8 ratio in PLWH.Methods: Plasma EVs subtype purified from PLWH and uninfected controls were sized using dynamic light scattering and quantified using flow cytometry and acetylcholine esterase (AChE) activity. Expression of mature miRNAs miR-92, miR-155, miR-223 was measured by quantitative reverse-transcriptase polymerase chain reaction in EVs and leucocytes.Results: HIV infection induces increased production of small EVs in plasma. EV subtypes were differentially enriched in miR-92, miR-155, and miR-223. Positive correlations between CD8 T-cell count and large EVs abundance and small EVs AChE activity were observed. CD4/CD8 ratio was negatively correlated with small EV AChE activity, and miRNA-155 level per small EV was negatively correlated with CD8 T-cell count.Conclusions: These findings suggest that quantifying large or small EVs and profiling miRNA content per EV might provide new functional biomarkers of immune activation and inflammation.
- Published
- 2020
17. Plasma Extracellular Vesicle Subtypes as Potential Biomarkers of Immune Activation in HIV-Infected Patients
- Author
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Mohammad-Ali Jenabian, Michel Alary, Julien Vitry, Jean-Pierre Routy, Benjamin Goyer, Wilfried Wenceslas Bazié, Cécile Tremblay, Caroline Gilbert, Julien Boucher, Patrick Provost, and Sylvie Trottier
- Subjects
business.industry ,T cell ,education ,CD4-CD8 Ratio ,Extracellular vesicle ,medicine.disease ,Systemic inflammation ,miR-155 ,medicine.anatomical_structure ,Immune system ,Acquired immunodeficiency syndrome (AIDS) ,Immunology ,medicine ,medicine.symptom ,business ,CD8 - Abstract
Chronic immune activation and systemic inflammation during HIV infection despite effective antiretroviral therapy (ART) is associate with non-AIDS co-morbidities in people living with HIV (PLWH). Previous studies have shown that plasma levels of extracellular vesicles (EVs) may be used as immune activation or inflammatory biomarkers of HIV disease progression. Several studies have focused on microRNA and mitochondrial DNA (mtDNA) levels reached concomitantly in immune cells and EVs. We hypothesized that large and small EVs could contain different amounts of microRNA and mtDNA and that could reflect immune activation associated with elevated CD8 T cell count or low CD4/CD8 ratio in PLWH receiving ART. Plasma EVs obtained from PLWH and uninfected control were sized using dynamic light scattering and quantified using flow cytometry. Expression of mature miR-92, miR-155, miR-223 and mtDNA was measured by qRT-PCR. Positive correlation have been observed between CD8+ T cell count and large EV abundance, AChE activity in small EVs and negative correlation with miR-155 levels in small EVs. CD4/CD8 ratio was positively correlated with large EVs abundance and negatively with AChE activity in small EVs and PMN-associated copies of miR-92. MicroRNA-155 level in small EVs were positively correlated with monocyte counts. MiR-155 and mtDNA contents of large EVs were increased more than miR-92 and miR-223 contents in small EVs. A positive correlation was observed between large EVs mtDNA content and CD4 T cell count. These findings suggest that profiling the microRNA and mtDNA contents of EV might provide new functional biomarkers of immune activation and inflammation. Funding Statement: This study was funded through Canadian Institutes of Health Research (CIHR) grants MOP 188726; MOP-267056 (HIV/AIDS initiative) to C.G., MOP-03230 to J.P.R. and to C.T. for the cohort establishment and CIHR Foundation Grant FDN-143218 to M.A. for the studentship awarded to W.W.B., as well as by the Fonds de recherche du Quebec – Sante (FRQ-S) AIDS and infectious diseases network. C.T. is an FRQ-S scholar and holder of the Pfizer/Universite de Montreal chair on HIV translational Research. J-P.R. holds the Louis Lowenstein chair in Hematology & Oncology at McGill University. M-A.J. holds a CIHR Canada Research Chair tier 2 in Immuno-Virology. The infrastructure of the Centre de recherche du CHU de Quebec – Universite Laval is supportes by the FRQ-S. Declaration of Interests: The authors declare that no competing interests exist. Ethics Approval Statement: This study received approval from the ethics review boards of Centre de recherche du CHU de Quebec, Quebec, Canada and the McGill University Health Centre, Montreal, Quebec, Canada. All subjects were anonymous volunteers and provided written informed consent to participate in the study.
- Published
- 2020
18. HIV persistence in mucosal CD4+ T cells within the lungs of adults receiving long-term suppressive antiretroviral therapy
- Author
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Omar Farnós, Ron Olivenstein, Marianna Orlova, Jean-Pierre Routy, Amélie Pagliuzza, Petronela Ancuta, Mohammad-Ali Jenabian, Erwin Schurr, Christina De Castro, Nicolas Chomont, Syim Salahuddin, Jean Bourbeau, and Cecilia T. Costiniuk
- Subjects
0301 basic medicine ,Senescence ,Adult ,CD4-Positive T-Lymphocytes ,Male ,Sustained Virologic Response ,Cellular differentiation ,030106 microbiology ,Immunology ,HIV persistence ,HIV Infections ,CD38 ,Polymerase Chain Reaction ,Flow cytometry ,03 medical and health sciences ,Basic Science ,medicine ,Immunology and Allergy ,Humans ,Respiratory system ,Intraepithelial Lymphocytes ,Lung ,lungs ,Aged ,pulmonary immunity ,medicine.diagnostic_test ,business.industry ,HIV ,Middle Aged ,Flow Cytometry ,Phenotype ,3. Good health ,030104 developmental biology ,Infectious Diseases ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Anti-Retroviral Agents ,DNA, Viral ,Female ,mucosal CD4+ T cells ,business - Abstract
Background: The lungs were historically identified as one of the major anatomic sites for HIV replication in the pre-antiretroviral therapy (ART) era. However, their contribution to HIV persistence in individuals under suppressive ART remains understudied. Design: We assessed HIV persistence and comprehensively characterized pulmonary mucosal CD4+ T cells in HIV-infected (HIV+) individuals receiving long-term suppressive ART versus uninfected participants. Methods: Bronchoalveolar lavage (BAL), bronchial biopsies, and matched peripheral blood were obtained from n = 24 HIV-infected adults receiving long-term suppressive ART (median: 9 years) and n = 8 healthy volunteers without respiratory symptoms. HIV-DNA and cell-associated HIV-RNA were quantified by ultra-sensitive PCR, and lung mucosal CD4+ T-cell subsets were characterized by multiparameter flow cytometry. Results: The levels of HIV-DNA were 13-fold higher in total BAL cells compared to blood. Importantly, FACS-sorted CD4+ T cells from BAL contained greater levels of HIV-DNA compared to peripheral CD4+ T cells. BAL CD4+ T cells in HIV+ individuals were characterized mostly by an effector memory phenotype, whereas naive and terminally differentiated cells were underrepresented compared to blood. Furthermore, BAL CD4+ T cells expressed higher levels of immune activation (HLA-DR/CD38) and senescence (CD57) markers. Importantly, BAL was enriched in T-cell subsets proposed to be preferential cellular HIV reservoirs, including memory CD4+CCR6+, Th1Th17 (CD4+CCR6+CCR4−CXCR3+), CD4+CCR6+CXCR3−CCR4−, and CD4+CD32a+ T cells. Conclusion: The pulmonary mucosa represents an important immunological effector site highly enriched in activated and preferential CD4+ T-cell subsets for HIV persistence during long-term ART in individuals without respiratory symptoms. Our findings raise new challenges for the design of novel HIV eradication strategies in mucosal tissues.
- Published
- 2018
19. Differential Dynamics of Regulatory T-Cell and Th17 Cell Balance in Mesenteric Lymph Nodes and Blood following Early Antiretroviral Initiation during Acute Simian Immunodeficiency Virus Infection
- Author
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Alexis Yero, Omar Farnós, Gina Racine, Jérôme Estaquier, Henintsoa Rabezanahary, and Mohammad-Ali Jenabian
- Subjects
simian immunodeficiency virus ,Regulatory T cell ,antiretroviral therapy ,Immunology ,Simian Acquired Immunodeficiency Syndrome ,Tregs ,chemical and pharmacologic phenomena ,C-C chemokine receptor type 6 ,Biology ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,Microbiology ,regulatory T cells ,immune dysfunction ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Fibrosis ,Virology ,medicine ,Animals ,Mesenteric lymph nodes ,030304 developmental biology ,Immunity, Cellular ,0303 health sciences ,Blood Cells ,human immunodeficiency virus ,virus diseases ,FOXP3 ,hemic and immune systems ,Simian immunodeficiency virus ,medicine.disease ,gut mucosal immunity ,CD4 Lymphocyte Count ,3. Good health ,medicine.anatomical_structure ,Lymphatic system ,Anti-Retroviral Agents ,Insect Science ,Th17 Cells ,Pathogenesis and Immunity ,mucosal immunity ,Lymph Nodes ,early antiretroviral therapy ,030215 immunology - Abstract
Tregs contribute to SIV/HIV disease progression by inhibition of antiviral specific responses and effector T-cell proliferation. Tregs also cause tissue fibrosis via transforming growth factor β1 production and collagen deposition, which are associated with microbial translocation and generalized immune activation. Early ARV initiation upon viral exposure is recommended globally and results in improved immune function recovery and reduced viral persistence. Here, using an acute SIV infection model of rhesus macaques, we demonstrated for the first time that despite clear improvements in mucosal CD4 T cells, in contrast to blood, Treg frequencies in MLNs remained elevated following early ARV initiation. The particular Th17/Treg balance observed in MLNs can contribute, in part, to the maintenance of mucosal fibrosis during suppressive ARV treatment. Our results provide a better understanding of gut mucosal immune dynamics following early ARV initiation. These findings suggest that Treg-based treatments could serve as a novel immunotherapeutic approach to decrease gut mucosal damage during SIV/HIV infections., Increased frequencies of immunosuppressive regulatory T cells (Tregs) are associated with gut lymphoid tissue fibrosis and dysfunction which, in turn, contribute to disease progression in chronic simian immunodeficiency virus/human immunodeficiency virus (SIV/HIV) infection. Mesenteric lymph nodes (MLNs), which drain the large and small intestine, are critical sites for the induction and maintenance of gut mucosal immunity. However, the dynamics of Tregs in MLNs are not well understood due to the lack of accessibility to these tissues in HIV-infected individuals. Here, the dynamics of Tregs in blood and MLNs were assessed in SIV-infected rhesus macaques (RMs) following early antiretroviral drug (ARV) initiation. Early ARV initiation reduced T-cell immune activation, as assessed by HLA-DR/CD39 expression, and prevented the depletion of memory CCR6+ Th17 cells in both blood and MLNs. Untreated animals showed higher frequencies of Tregs, CD39+ Tregs, thymic Tregs, and new memory CD4 populations sharing similarity with Tregs as CTLA4+ PD1– and CTLA4+ PD1– FoxP3+ T cells. Despite early ARV treatment, the frequencies of these Treg subsets remained unchanged within the MLNs and, in contrast to blood normalization, the Th17/Treg ratio remained distorted in MLNs. Furthermore, our results highlighted that the expressions of IDO-1, TGFβ1 and collagen-1 mRNA remained unchanged in MLN of ARV-treated RMs. ARV interruption did not affect T-cell immune activation and Th17/Treg ratios in MLN. Altogether, our data demonstrated that early ARV initiation within the first few days of SIV infection is unable to reduce the frequencies and homing of various subsets of Tregs within the MLNs which, in turn, may result in tissue fibrosis, impairment in MLN function, and HIV persistence. IMPORTANCE Tregs contribute to SIV/HIV disease progression by inhibition of antiviral specific responses and effector T-cell proliferation. Tregs also cause tissue fibrosis via transforming growth factor β1 production and collagen deposition, which are associated with microbial translocation and generalized immune activation. Early ARV initiation upon viral exposure is recommended globally and results in improved immune function recovery and reduced viral persistence. Here, using an acute SIV infection model of rhesus macaques, we demonstrated for the first time that despite clear improvements in mucosal CD4 T cells, in contrast to blood, Treg frequencies in MLNs remained elevated following early ARV initiation. The particular Th17/Treg balance observed in MLNs can contribute, in part, to the maintenance of mucosal fibrosis during suppressive ARV treatment. Our results provide a better understanding of gut mucosal immune dynamics following early ARV initiation. These findings suggest that Treg-based treatments could serve as a novel immunotherapeutic approach to decrease gut mucosal damage during SIV/HIV infections.
- Published
- 2019
20. Characterization of myeloid cell populations in human testes collected after sex reassignment surgery
- Author
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Rosalie Ponte, Nicole F. Bernard, Jean-Pierre Routy, Pierre Brassard, Vikram Mehraj, Ekaterina Yurchenko, Fadi Brimo, Maud Bélanger, Franck P. Dupuy, and Mohammad-Ali Jenabian
- Subjects
Adult ,Male ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Myeloid ,Hormone Replacement Therapy ,CD14 ,Sialic Acid Binding Ig-like Lectin 3 ,Immunology ,Cell ,Interleukin-3 Receptor alpha Subunit ,Lipopolysaccharide Receptors ,Antigens, Differentiation, Myelomonocytic ,Receptors, Cell Surface ,Inflammation ,Spironolactone ,Biology ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Immune privilege ,Antigens, CD ,Testis ,Sex Reassignment Surgery ,medicine ,Humans ,Immunology and Allergy ,Progesterone ,CD11b Antigen ,030219 obstetrics & reproductive medicine ,Estradiol ,medicine.diagnostic_test ,Macrophages ,Myeloid-Derived Suppressor Cells ,Obstetrics and Gynecology ,Dendritic Cells ,Middle Aged ,030104 developmental biology ,medicine.anatomical_structure ,Reproductive Medicine ,Hormonal therapy ,medicine.symptom ,Orchiectomy ,CD163 - Abstract
The testis has been described in animal models as a site of immune privilege, which protects spermatids against tissue damage during inflammation. Myeloid cells, including macrophages and dendritic cells (DC), are defined as key players in the testicular immune privilege in animal models. However, their distribution and frequency in human testis remain poorly described. To overcome the challenges related to tissue sampling, we obtained testicular tissue from men under hormonal therapy who elected to have sex reassignment surgery (SRS). We examined the distribution of myeloid cell populations in tissue sections using immunohistofluorescence and evaluated their relative frequencies in fresh testicular cell suspensions compared with matched blood using multi-parametric flow cytometry. We identified 4.9% of CD45+ leucocytes in testicular cell suspensions, of which 0.4% were B cells, demonstrating a low level of blood contamination. Myeloid cells (Lin-HLA-DR+) were located in the testicular interstitium and represented a median of 23.4% of testicular leucocytes, displaying higher HLA-DR expression compared to their counterparts in blood (p=0.001). The frequency of testicular myeloid cells was not linked with the duration of hormonal therapy. Resident macrophages (CD14+CD163+) constituted the most frequent myeloid cell subset and expressed high levels of CD163. Elevated proportion of myeloid DC (CD14-CD11c+) contrasted with the paucity of plasmacytoid DC (CD14-CD123+) in testis. Myeloid-derived suppressor cells (Lin-HLA-DR-CD33hiCD11bhi) were not detected in the testis while constituting 0.5% of blood leucocytes. For the first time, we characterized myeloid cell subsets in human testes collected after SRS, providing a basis to assess their contribution to immune privilege.
- Published
- 2018
21. CTN 328: immunogenicity outcomes in people living with HIV in Canada following vaccination for COVID-19 (HIV-COV): protocol for an observational cohort study
- Author
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Cecilia T Costiniuk, Joel Singer, Marc-André Langlois, Iva Kulic, Judy Needham, Ann Burchell, Mohammad-Ali Jenabian, Sharon Walmsley, Mario Ostrowski, Colin Kovacs, Darrell Tan, Marianne Harris, Mark Hull, Zabrina Brumme, Mark Brockman, Shari Margolese, Enrico Mandarino, Jonathan B Angel, Jean-Pierre Routy, Aslam H Anis, and Curtis Cooper
- Subjects
Canada ,COVID-19 Vaccines ,SARS-CoV-2 ,Vaccination ,COVID-19 ,HIV & AIDS ,HIV Infections ,General Medicine ,virology ,Cohort Studies ,immunology ,Observational Studies as Topic ,Humans ,Multicenter Studies as Topic ,HIV/AIDS ,Diterpenes - Abstract
IntroductionMost existing vaccines require higher or additional doses or adjuvants to provide similar protection for people living with HIV (PLWH) compared with HIV-uninfected individuals. Additional research is necessary to inform COVID-19 vaccine use in PLWH.Methods and analysisThis multicentred observational Canadian cohort study will enrol 400 PLWH aged>16 years from Montreal, Ottawa, Toronto and Vancouver. Subpopulations of PLWH of interest will include individuals: (1) >55 years of age; (2) with CD4 counts 3; (3) with multimorbidity (>2 comorbidities) and (4) ‘stable’ or ‘reference’ PLWH (CD4 T cells >350 cells/mm3, suppressed viral load for>6 months and<1 comorbidity). Data for 1000 HIV-negative controls will be obtained via a parallel cohort study (Stop the Spread Ottawa), using similar time points and methods. Participants receiving>1 COVID-19 vaccine will attend five visits: prevaccination; 1 month following the first vaccine dose; and at 3, 6 and 12 months following the second vaccine dose. The primary end point will be the percentage of PLWH with COVID-19-specific antibodies at 6 months following the second vaccine dose. Humoral and cell-mediated immune responses, and the interplay between T cell phenotypes and inflammatory markers, will be described. Regression techniques will be used to compare COVID-19-specific immune responses to determine whether there are differences between the ‘unstable’ PLWH group (CD4 Ethics and disseminationResearch ethics boards at all participating institutions have granted ethics approval for this study. Written informed consent will be obtained from all study participants prior to enrolment. The findings will inform the design of future COVID-19 clinical trials, dosing strategies aimed to improve immune responses and guideline development for PLWH.Trial registration numberNCT04894448.
- Published
- 2021
22. Differential synthesis and release of IL-18 and IL-18 Binding Protein from human platelets and their implications for HIV infection
- Author
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Devendra Amre, Jean-Pierre Routy, Cécile Tremblay, Mohammad-Ali Jenabian, Suzanne Samarani, Ossama Allam, and Ali Ahmad
- Subjects
Blood Platelets ,Male ,0301 basic medicine ,medicine.medical_treatment ,Immunology ,Caspase 1 ,HIV Infections ,Biology ,Biochemistry ,03 medical and health sciences ,Thrombin ,medicine ,Humans ,Immunology and Allergy ,Platelet ,Platelet activation ,Molecular Biology ,Secretory Vesicles ,Binding protein ,Interleukin-18 ,Inflammasome ,Hematology ,Molecular biology ,3. Good health ,030104 developmental biology ,Cytokine ,Gene Expression Regulation ,HIV-1 ,Intercellular Signaling Peptides and Proteins ,Female ,Interleukin 18 ,K562 Cells ,medicine.drug - Abstract
IL-18 is a pro-inflammatory cytokine belonging to the IL-1 family and is produced in the body from macrophages, epithelial and dendritic cells, keratinocytes, adrenal cortex etc. The cytokine is produced as an inactive precursor that is cleaved inside cells into its mature form by activated caspase 1, which exists as an inactive precursor in human cells and requires assembly of an inflammasomes for its activation. We show here for the first time that human platelets contain transcripts for the IL-18 gene. They synthesize the cytokine de novo, process and release it upon activation. The activation also results in the assembly of an inflammasome and activation of caspase-1. Platelets also contain the IL-18 antagonist, the IL-18-Binding Protein (IL-18BP); however, it is not synthesized in them de novo, is present in pre-made form and is released irrespective of platelet activation. IL-18 and IL-18BP co-localize to α granules inside platelets and are secreted out with different kinetics. Platelet activation contributes to plasma concentrations in healthy individuals, as their plasma samples contain abundant IL-18, while their platelet-poor plasma samples contain very little amounts of the cytokine. The plasma and PPP samples from these donors, however, contain comparable amounts of IL-18BP. Unlike healthy individuals, the platelet-poor plasma from HIV-infected individuals contains significant amounts of IL-18. Our findings have important implications for viral infections and other human diseases that are accompanied by platelet activation.
- Published
- 2017
23. A potentially protective role of IL-18 Binding Protein in HIV-infected Long-Term Non-Progressors
- Author
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Devendra Amre, Vikram Mehraj, Ossama Allam, Alexandre Iannello, Jean-Pierre Routy, Cécile Tremblay, Ali Ahmad, Mohammad-Ali Jenabian, and Suzanne Samarani
- Subjects
Male ,0301 basic medicine ,Acquired Immunodeficiency Syndrome ,Binding protein ,Immunology ,Antagonist ,Hematology ,Biology ,Biochemistry ,CD4 Lymphocyte Count ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Hiv infected ,HIV-1 ,Humans ,Intercellular Signaling Peptides and Proteins ,Immunology and Allergy ,Female ,Interleukin 18 ,Molecular Biology ,Viral load - Abstract
An imbalance between IL-18 and its antagonist, IL-18 Binding Protein, occurs in the circulation of HIV-infected individuals. We show here for the first time that HIV-infected Long Term Non-Progressors (LTNPs) do not develop this imbalance, and maintain normal levels of IL-18BP in the circulation. Their circulating levels of the antagonist correlate negatively with viral loads and show a positive trend with CD4+ T cells counts. The maintenance of normal production of IL-18BP may contribute, at least in part, to the ability of LTNPs to delay AIDS progression.
- Published
- 2017
24. Reply to: Benefits of cannabis use for metabolic disorders and survival in people living with HIV with or without hepatitis C
- Author
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Mohammad-Ali Jenabian and Cecilia T. Costiniuk
- Subjects
medicine.medical_specialty ,biology ,business.industry ,Immunology ,Human immunodeficiency virus (HIV) ,MEDLINE ,Hepatitis C ,Cannabis use ,medicine.disease_cause ,biology.organism_classification ,medicine.disease ,Infectious Diseases ,medicine ,Immunology and Allergy ,Cannabis ,business ,Psychiatry - Published
- 2020
25. HIV Diversity and Genetic Compartmentalization in Blood and Testes during Suppressive Antiretroviral Therapy
- Author
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Bradley R Jones, Vikram Mehraj, Pierre Brassard, Mohammad-Ali Jenabian, Nicolas Chomont, Jean-Pierre Routy, Fredrick H. Omondi, Zabrina L. Brumme, Natalie N. Kinloch, Rachel L Miller, Jeffrey B. Joy, Franck P. Dupuy, Art F. Y. Poon, Rosalie Ponte, and Rémi Fromentin
- Subjects
Male ,Immunology ,Human immunodeficiency virus (HIV) ,HIV Infections ,Biology ,medicine.disease_cause ,Microbiology ,Clonal Evolution ,03 medical and health sciences ,0302 clinical medicine ,Virology ,Testis ,medicine ,Sex Reassignment Surgery ,Humans ,nef Gene Products, Human Immunodeficiency Virus ,Phylogeny ,030304 developmental biology ,Subgenomic mRNA ,0303 health sciences ,Mutation ,Phylogenetic tree ,Mechanism (biology) ,Sequence Analysis, RNA ,virus diseases ,Genetic Variation ,Compartmentalization (psychology) ,Antiretroviral therapy ,3. Good health ,Real-time polymerase chain reaction ,Genetic Diversity and Evolution ,Anti-Retroviral Agents ,Elective Surgical Procedures ,030220 oncology & carcinogenesis ,Insect Science ,Case-Control Studies ,HIV-1 - Abstract
HIV's ability to persist during suppressive antiretroviral therapy is the main barrier to cure. Immune-privileged tissues, such as the testes, may constitute distinctive sites of HIV persistence, but this has been challenging to study in humans. We analyzed the proviral burden and genetics in the blood and testes of 10 individuals on suppressive therapy who underwent elective gender-affirming surgery. HIV DNA levels in matched blood and testes were quantified by quantitative PCR, and subgenomic proviral sequences (nef region) were characterized from single templates. HIV diversity, compartmentalization, and immune escape burden were assessed using genetic and phylogenetic approaches. Diverse proviruses were recovered from the blood (396 sequences; 354 nef-intact sequences) and testes (326 sequences; 309 nef-intact sequences) of all participants. Notably, the frequency of identical HIV sequences varied markedly between and within individuals. Nevertheless, proviral loads, within-host unique HIV sequence diversity, and the immune escape burden correlated positively between blood and testes. When all intact nef sequences were evaluated, 60% of participants exhibited significant blood-testis genetic compartmentalization, but none did so when the evaluation was restricted to unique sequences per site, suggesting that compartmentalization, when present, is attributable to the clonal expansion of HIV-infected cells. Our observations confirm the testes as a site of HIV persistence and suggest that individuals with larger and more diverse blood reservoirs will have larger and more diverse testis reservoirs. Furthermore, while the testis microenvironment may not be sufficiently unique to facilitate the seeding of unique viral populations therein, differential clonal expansion dynamics may be at play, which may complicate HIV eradication. IMPORTANCE Two key questions in HIV reservoir biology are whether immune-privileged tissues, such as the testes, harbor distinctive proviral populations during suppressive therapy and, if so, by what mechanism. While our results indicated that blood-testis HIV genetic compartmentalization was reasonably common (60%), it was always attributable to differential frequencies of identical HIV sequences between sites. No blood-tissue data set retained evidence of compartmentalization when only unique HIV sequences per site were considered; moreover, HIV immune escape mutation burdens were highly concordant between sites. We conclude that the principal mechanism by which blood and testis reservoirs differ is not via seeding of divergent HIV sequences therein but, rather, via differential clonal expansion of latently infected cells. Thus, while viral diversity and escape-related barriers to HIV eradication are of a broadly similar magnitude across the blood and testes, clonal expansion represents a challenge. The results support individualized analysis of within-host reservoir diversity to inform curative approaches.
- Published
- 2019
26. Processing of Bronchoalveolar Lavage Fluid and Matched Blood for Alveolar Macrophage and CD4+ T-cell Immunophenotyping and HIV Reservoir Assessment
- Author
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Oussama Meziane, Mohammad-Ali Jenabian, Ron Olivenstein, Cecilia T. Costiniuk, Nicolas Chomont, Syim Salahuddin, Omar Farnós, Elaine Thomson, and Amélie Pagliuzza
- Subjects
0301 basic medicine ,Disease reservoir ,Lung ,General Immunology and Microbiology ,medicine.diagnostic_test ,business.industry ,General Chemical Engineering ,General Neuroscience ,Context (language use) ,respiratory system ,General Biochemistry, Genetics and Molecular Biology ,Flow cytometry ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Bronchoalveolar lavage ,Immunophenotyping ,Immune system ,medicine.anatomical_structure ,Immunology ,medicine ,Alveolar macrophage ,business ,030215 immunology - Abstract
Bronchoscopy is a medical procedure whereby normal saline is injected into the lungs via a bronchoscope and then suction is applied, removing bronchoalveolar lavage (BAL) fluid. The BAL fluid is rich in cells and can thus provide a 'snapshot' of the pulmonary immune milieu. CD4 T cells are the best characterized HIV reservoirs, while there is strong evidence to suggest that tissue macrophages, including alveolar macrophages (AMs), also serve as viral reservoirs. However, much is still unknown about the role of AMs in the context of HIV reservoir establishment and maintenance. Therefore, developing a protocol for processing BAL fluid to obtain cells that may be used in virological and immunological assays to characterize and evaluate the cell populations and subsets within the lung is relevant for understanding the role of the lungs as HIV reservoirs. Herein, we describe such a protocol, employing standard techniques such as simple centrifugation and flow cytometry. The CD4 T cells and AMs may then be used for subsequent applications, including immunophenotyping and HIV DNA and RNA quantification.
- Published
- 2019
27. The plasma levels of soluble ST2 as a marker of gut mucosal damage in early HIV infection
- Author
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Cécile Tremblay, Réjean Thomas, Bertrand Lebouché, Cecilia T. Costiniuk, Joseph Cox, Mohammad-Ali Jenabian, Jean-Pierre Routy, Rosalie Ponte, Roger LeBlanc, Jean-Guy Baril, and Vikram Mehraj
- Subjects
Adult ,Male ,0301 basic medicine ,microbial translocation ,T-Lymphocytes ,Immunology ,Interleukin-1 Receptor-Like 1 Protein ,Human immunodeficiency virus (HIV) ,HIV Infections ,Inflammation ,Biology ,Lymphocyte Activation ,medicine.disease_cause ,Plasma ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,early HIV infection ,Intestinal mucosa ,medicine ,Humans ,Immunology and Allergy ,soluble suppression of tumorigenicity 2 ,Lymphocyte Count ,Intestinal Mucosa ,Receptor ,Clinical Science ,Middle Aged ,Viral Load ,Interleukin-33 ,kynurenine ,3. Good health ,Interleukin 33 ,Cross-Sectional Studies ,030104 developmental biology ,Infectious Diseases ,Bacterial Translocation ,030220 oncology & carcinogenesis ,IL-33 ,Female ,epithelial gut damage ,CD8+ T-cell ,medicine.symptom ,Decoy ,Viral load - Abstract
Objective: Following tissue barrier breaches, interleukin-33 (IL-33) is released as an ‘alarmin’ to induce inflammation. Soluble suppression of tumorigenicity 2 (sST2), as an IL-33 decoy receptor, contributes to limit inflammation. We assessed the relationship between the IL-33/ST2 axis and markers of gut mucosal damage in patients with early (EHI) and chronic HIV infection (CHI) and elite controllers. Design: Analyses on patients with EHI and CHI were conducted to determine IL-33/sST2 changes over time. Methods: IL-33 and sST2 levels were measured in plasma. Correlations between sST2 levels and plasma viral load, CD4+ and CD8+ T-cell counts, expression of T-cell activation/exhaustion markers, gut mucosal damage, microbial translocation and inflammation markers, as well as kynurenine/tryptophan ratio were assessed. Results: Plasma sST2 levels were elevated in EHI compared with untreated CHI and uninfected controls, whereas IL-33 levels were comparable in all groups. In EHI, sST2 levels were positively correlated with the CD8+ T-cell count and the percentage of T cells expressing activation and exhaustion markers, but not with viral load or CD4+ T-cell count. Plasma sST2 levels also correlated with plasma levels of gut mucosal damage, microbial translocation and kynurenine/tryptophan ratio and for some markers of inflammation. Prospective analyses showed that early antiretroviral therapy had no impact on sST2 levels, whereas longer treatment duration initiated during CHI normalized sST2. Conclusion: As sST2 levels were elevated in EHI and were correlated with CD8+ T-cell count, immune activation, and microbial translocation, sST2 may serve as a marker of disease progression, gut damage and may directly contribute to HIV pathogenesis.
- Published
- 2016
28. Influence of Hepatitis C Virus Sustained Virological Response on Immunosuppressive Tryptophan Catabolism in ART-Treated HIV/HCV Coinfected Patients
- Author
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Ido P. Kema, Mohammad-Ali Jenabian, Kathleen Rollet, Robert Paulino Ramirez, Jean-Pierre Routy, Cecilia T. Costiniuk, Kishanda Vyboh, Vikram Mehraj, Marina B. Klein, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Lifestyle Medicine (LM)
- Subjects
0301 basic medicine ,Male ,HIV Infections ,Hepacivirus ,medicine.disease_cause ,chemistry.chemical_compound ,Liver disease ,0302 clinical medicine ,ANTIRETROVIRAL THERAPY ,Insulin ,Pharmacology (medical) ,Indoleamine 2,3-dioxygenase ,MICROBIAL TRANSLOCATION ,Kynurenine ,INSULIN-RESISTANCE ,Coinfection ,Tryptophan ,virus diseases ,Hepatitis C ,Middle Aged ,3. Good health ,Infectious Diseases ,HUMAN-IMMUNODEFICIENCY-VIRUS ,HCV ,Disease Progression ,030211 gastroenterology & hepatology ,Female ,Adult ,Anti-HIV Agents ,Hepatitis C virus ,Biology ,DENDRITIC CELLS ,03 medical and health sciences ,KYNURENINE PATHWAY ,co-infection ,HIV-INFECTION ,medicine ,Humans ,REGULATORY T-CELLS ,Inflammation ,Basic and Translational Science ,Catabolism ,Ribavirin ,3-DIOXYGENASE ,HIV ,NATURAL-HISTORY ,Immune dysregulation ,medicine.disease ,digestive system diseases ,3-dioxygenase 1 ,030104 developmental biology ,chemistry ,Immunology ,indoleamine 2 ,indoleamine 2,3-dioxygenase 1 ,INDOLEAMINE 2,3-DIOXYGENASE ,Biomarkers - Abstract
Background:We previously reported an association between tryptophan (Trp) catabolism and immune dysfunction in HIV monoinfection. Coinfection with HIV is associated with more rapid evolution of hepatitis C virus (HCV)-associated liver disease despite antiretroviral therapy (ART), possibly due to immune dysregulation. We hypothesized that liver fibrosis in HIV/HCV coinfection would be associated with immune dysfunction and alterations in Trp metabolism.Methods:Trp catabolism and inflammatory soluble markers were assessed in plasma samples from ART-treated HIV/HCV-coinfected patients (n = 90) compared with ART-treated HIV-monoinfected patients and noninfected subjects. Furthermore, 17 additional coinfected patients with sustained virological response (SVR) were assessed longitudinally 6 months after completion of interferon-alpha/ribavirin treatment.Results:HIV/HCV patients had higher Trp catabolism compared with HIV-monoinfected and healthy individuals. Elevated kynurenine levels in HIV/HCV patients with liver fibrosis correlated with the prognostic aspartate aminotransaminase to platelet ratio (APRI scores) and insulin levels. Furthermore, HIV/HCV patients had elevated levels of disease progression markers interleukin-6 and induced protein 10 and shared similar levels of markers of microbial translocation (intestinal fatty acid-binding protein, soluble CD14 and lipopolysaccharide-binding protein) compared with HIV-monoinfected and healthy individuals. Successful HCV treatment improved APRI score and markers of disease progression and microbial translocation although elevated Trp catabolism remained unchanged 6 months after SVR.Conclusion:ART-treated HIV/HCV-coinfected patients had elevated immunosuppressive Trp catabolism when compared with monoinfected HIV-treated patients, which did not normalize after SVR. These findings suggest that a necroinflammatory liver syndrome persists through inflammation by Trp catabolism after 6 month of SVR.
- Published
- 2016
29. Elevated Abundance, Size, and MicroRNA Content of Plasma Extracellular Vesicles in Viremic HIV-1+ Patients: Correlations With Known Markers of Disease Progression
- Author
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Caroline Subra, Caroline Gilbert, Jean-Pierre Routy, Patrick Provost, Cécile Tremblay, Pierre-François Tremblay Labrecque, Mohammad-Ali Jenabian, Benoit Laffont, and Audrey Hubert
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Male ,Anti-HIV Agents ,Cell ,CD4-CD8 Ratio ,Inflammation ,HIV Infections ,exosomes ,Biology ,CD8-Positive T-Lymphocytes ,Exosome ,miR-155 ,Pathogenesis ,03 medical and health sciences ,Extracellular Vesicles ,0302 clinical medicine ,Western blot ,microRNA ,medicine ,Humans ,Pharmacology (medical) ,Viremia ,030304 developmental biology ,0303 health sciences ,Basic and Translational Science ,medicine.diagnostic_test ,Middle Aged ,CD4/CD8 T-cell ratio ,miR-223 ,Microvesicles ,3. Good health ,MicroRNAs ,Infectious Diseases ,medicine.anatomical_structure ,inflammation ,030220 oncology & carcinogenesis ,Immunology ,HIV-1 ,biomarker ,Female ,medicine.symptom ,DAP-3 ,microvesicles ,CD8 ,Biomarkers - Abstract
Background Because of factors only partly understood, the generalized elevated immune activation and inflammation characterizing HIV-1-infected patients are corrected incompletely with antiretroviral therapy (ART). Extracellular vesicles (EVs) including exosomes and microvesicles released by several cell types may contribute to immune activation and dysfunction. EV size, abundance, and content appear to differ according to infection phase, disease progression, and ART. Methods We examined whether the size of EVs and the abundance of exosomes in plasma are associated with cell and tissue activation as well as with viral production. Acetylcholinesterase-bearing (AChE+) exosomes in plasma were quantified using an AChE assay. EV size was analyzed using dynamic light scattering. Proteins and microRNAs present in EVs were detected by Western blot and real-time polymerase chain reaction, respectively. Results Exosomes were found more abundant in the plasma of ART-naive patients. EV size was larger in ART-naive than in ART-suppressed patients, elite controllers, or healthy control subjects. Both exosome abundance and EV sizes were inversely correlated with CD4/CD8 T-cell ratio and neutrophil, platelet, and CD4 T-cell counts and positively correlated with CD8 T-cell counts. A negative correlation was found between CD4 T-cell nadir and exosome abundance, but not EV size. Levels of miR-155 and miR-223 but not miR-92 were strongly correlated negatively with EV abundance and size in ART-naive patients. Conclusions Monitoring of circulating EVs and EV-borne microRNA is possible and may provide new insight into HIV-1 pathogenesis, disease progression, and the associated inflammatory state, as well as the efficacy of ART and the treatments intended to reduce immune activation.
- Published
- 2015
30. Differential influence of race and environment on indeterminate reactivities to non-treponemal and treponemal antigens by immuno-chromatographic dual syphilis rapid test
- Author
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Ginette Claude Mireille Kalla, Laurent Bélec, Frédéric Talla, Mohammad-Ali Jenabian, Esther Voundi Voundi, François-Xavier Mbopi-Kéou, Ralph-Sydney Mboumba Bouassa, and Fru Angwafo
- Subjects
030231 tropical medicine ,Black People ,White People ,03 medical and health sciences ,Race (biology) ,0302 clinical medicine ,Antigen ,Medicine ,Humans ,False Positive Reactions ,030212 general & internal medicine ,Cameroon ,Prospective Studies ,Syphilis ,Treponema pallidum ,race ,Rapid testing ,Antigens, Bacterial ,immuno-chromatographic rapid test ,Central Africa ,business.industry ,Research ,Central africa ,General Medicine ,False positivity ,medicine.disease ,false positivity ,Test (assessment) ,Syphilis Serodiagnosis ,Immunology ,France ,business ,Indeterminate ,environment - Abstract
Introduction Syphilis rapid test results may be influenced by numerous environmental and genetic factors. Methods The proportion of false positive syphilis non-treponemal (NT) and treponemal (T) test results using immuno-chromatographic dual syphilis rapid test on serum from Cameroonian blacks (n=103) versus French blacks (n=104) or French caucasians (n=51), all HIV-negative and free of clinical syphilis, was examined. Results Black individuals in Cameroon had a significantly higher frequency of false positive NT or T tests than black individuals in France. black individuals in France had a higher frequency of indeterminate NT tests as compared to caucasians in France. Conclusion Both racial and environmental factors may affect immuno-chromatographic dual syphilis rapid testing.
- Published
- 2018
31. Anti-Gag antibodies gag HIV infection and slow disease progression
- Author
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Mohammad-Ali Jenabian, Cécile Tremblay, Ali Ahmad, Jean-Pierre Routy, and Vikram Mehraj
- Subjects
0301 basic medicine ,biology ,business.industry ,viruses ,Immunology ,Human immunodeficiency virus (HIV) ,virus diseases ,HIV Infections ,medicine.disease_cause ,Virology ,gag Gene Products, Human Immunodeficiency Virus ,Article ,03 medical and health sciences ,030104 developmental biology ,Infectious Diseases ,Immunoglobulin G ,biology.protein ,Disease Progression ,HIV-1 ,Immunology and Allergy ,Medicine ,Humans ,Antibody ,Slow disease progression ,business - Abstract
OBJECTIVE: Post-infection HIV viral control and immune correlates analysis of the RV144 vaccine trial indicate a potentially critical role for Fc receptor-mediated antibody functions. However, the influence of functional antibodies in clade C infection is largely unknown. DESIGN: Plasma samples from 361 chronic subtype C-infected, antiretroviral therapy-naïve participants were tested for their HIV-specific isotype and subclass distributions, along with their Fc receptor-mediated functional potential. METHOD: Total IgG, IgG subclasses and IgA binding to p24 clade B/C and gp120 consensus C proteins were assayed by multiplex. Antibody-dependent uptake of antigen-coated beads and Fc receptor-mediated NK cell degranulation were evaluated as surrogates for antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) respectively. RESULTS: p24 IgG1 was the only subclass associated with viral control (p=0.01), with higher p24-specific ADCP and ADCC responses detected in individuals with high p24 IgG1. Although p24 IgG1 levels were enriched in subjects with elevated Gag-specific T cell responses, these levels remained an independent predictor of low viral loads (p=0.04) and high CD4 counts (p=0.004) after adjusting for Gag-specific T cell responses and for protective HLA class I alleles. CONCLUSION: p24 IgG1 levels independently predict viral control in HIV-1 clade C infection. Whether these responses contribute to direct antiviral control via the recruited killing of infected cells via the innate immune system or simply mark a qualitatively superior immune response to HIV, is uncertain, but highlights the role of p24-specific antibodies in control of clade C HIV-1 infection.
- Published
- 2018
32. Immune Suppression by Myeloid Cells in HIV Infection: New Targets for Immunotherapy
- Author
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Vikram Mehraj, Jean-Pierre Routy, Mohammad-Ali Jenabian, and Kishanda Vyboh
- Subjects
Myeloid ,T cell ,medicine.medical_treatment ,Viral pathogenesis ,Inflammation ,neutrophils ,myeloid derived suppressor cells ,Article ,Immune system ,Virology ,Dendritic cells (DCs) ,Medicine ,Macrophage ,business.industry ,Public Health, Environmental and Occupational Health ,HIV ,Immunotherapy ,macrophages ,3. Good health ,Infectious Diseases ,medicine.anatomical_structure ,Immunology ,Myeloid-derived Suppressor Cell ,immunotherapy ,medicine.symptom ,monocytes ,business - Abstract
Over thirty years of extensive research has not yet solved the complexity of HIV pathogenesis leading to a continued need for a successful cure. Recent immunotherapy-based approaches are aimed at controlling the infection by reverting immune dysfunction. Comparatively less appreciated than the role of T cells in the context of HIV infection, the myeloid cells including macrophages monocytes, dendritic cells (DCs) and neutrophils contribute significantly to immune dysfunction. Host restriction factors are cellular proteins expressed in these cells which are circumvented by HIV. Guided by the recent literature, the role of myeloid cells in HIV infection will be discussed highlighting potential targets for immunotherapy. HIV infection, which is mainly characterized by CD4 T cell dysfunction, also manifests in a vicious cycle of events comprising of inflammation and immune activation. Targeting the interaction of programmed death-1 (PD-1), an important regulator of T cell function; with PD-L1 expressed mainly on myeloid cells could bring promising results. Macrophage functional polarization from pro-inflammatory M1 to anti-inflammatory M2 and vice versa has significant implications in viral pathogenesis. Neutrophils, recently discovered low density granular cells, myeloid derived suppressor cells (MDSCs) and yolk sac macrophages provide new avenues of research on HIV pathogenesis and persistence. Recent evidence has also shown significant implications of neutrophil extracellular traps (NETs), antimicrobial peptides and opsonizing antibodies. Further studies aimed to understand and modify myeloid cell restriction mechanisms have the potential to contribute in the future development of more effective anti-HIV interventions that may pave the way to viral eradication.
- Published
- 2014
33. Cell-to-cell transfer of HIV infection: implications for HIV viral persistence
- Author
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Cecilia T. Costiniuk and Mohammad-Ali Jenabian
- Subjects
CD4-Positive T-Lymphocytes ,Central Nervous System ,Male ,Cell type ,Immunological Synapses ,Cell ,Human immunodeficiency virus (HIV) ,HIV Infections ,Biology ,medicine.disease_cause ,Immune system ,Pregnancy ,Virology ,medicine ,Humans ,Disease Reservoirs ,Infectious disease transmission ,Transmission (medicine) ,Macrophages ,HIV ,virus diseases ,Dendritic Cells ,Virological synapse ,Infectious Disease Transmission, Vertical ,Gastrointestinal Tract ,Kidney Tubules ,medicine.anatomical_structure ,Immunology ,Female ,Viral persistence - Abstract
A major research priority for HIV eradication is the elucidation of the events involved in HIV reservoir establishment and persistence. Cell-to-cell transmission of HIV represents an important area of study as it allows for the infection of cell types which are not easily infected by HIV, leading to the establishment of long-lived viral reservoirs. This phenomenon enables HIV to escape elimination by the immune system. This process may also enable HIV to escape suppressive effects of anti-retroviral drugs. During cell-to-cell transmission of HIV, a dynamic series of events ensues at the virological synapse that promotes viral dissemination. Cell-to-cell transmission involves various types of cells of the immune system and this mode of transmission has been shown to have an important role in sexual and mother-to-child transmission of HIV and spread of HIV within the central nervous system and gut-associated lymphoid tissues. There is also evidence that cell-to-cell transmission of HIV occurs between thymocytes and renal tubular cells. Herein, following a brief review of the processes involved at the virological synapse, evidence supporting the role for cell-to-cell transmission of HIV in the maintenance of the HIV reservoir will be highlighted. Therapeutic considerations and future directions for this area of research will also be discussed.
- Published
- 2014
34. Combination antiretroviral therapy and indoleamine 2,3-dioxygenase in HIV infections
- Author
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Vikram Mehraj, Ali Ahmad, Mohammad-Ali Jenabian, Jean-Pierre Routy, Cécile Tremblay, and Suzanne Samarani
- Subjects
0301 basic medicine ,business.industry ,Immunology ,Human immunodeficiency virus (HIV) ,medicine.disease_cause ,Antiretroviral therapy ,03 medical and health sciences ,030104 developmental biology ,Infectious Diseases ,Immunology and Allergy ,Medicine ,Indoleamine 2,3-dioxygenase ,business - Published
- 2016
35. Potential for False-Positive Results with Serological Assays for HIV in Central Africa: Implications for the HIV Serodiagnosis Algorithm According to the 2015 Consolidated WHO Recommendations for Resource-Constrained Countries
- Author
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Ralph Sydey Mboumba Bouassa, Cecilia T. Costiniuk, Laurent Bélec, Leman Robin, Perrine Talla, Serge Tonen Wolyec, and Mohammad-Ali Jenabian
- Subjects
0301 basic medicine ,medicine.medical_specialty ,030106 microbiology ,Immunology ,Resource constrained ,Human immunodeficiency virus (HIV) ,MEDLINE ,HIV Infections ,medicine.disease_cause ,World Health Organization ,Sensitivity and Specificity ,Serology ,03 medical and health sciences ,0302 clinical medicine ,Who recommendations ,Virology ,medicine ,Humans ,Africa, Central ,False Positive Reactions ,030212 general & internal medicine ,business.industry ,Central africa ,AIDS Serodiagnosis ,Reproducibility of Results ,Infectious Diseases ,Family medicine ,HIV-1 ,business ,Algorithms - Published
- 2017
36. HIV induces production of IL-18 from intestinal epithelial cells that increases intestinal permeability and microbial translocation
- Author
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Cécile Tremblay, Vikram Mehraj, Devendra Amre, Jean-Pierre Routy, Ossama Allam, Ali Ahmad, Suzanne Samarani, and Mohammad-Ali Jenabian
- Subjects
0301 basic medicine ,Male ,RNA viruses ,Physiology ,medicine.medical_treatment ,lcsh:Medicine ,HIV Infections ,Apoptosis ,Occludin ,Pathology and Laboratory Medicine ,Epithelium ,0302 clinical medicine ,Immunodeficiency Viruses ,Animal Cells ,Immune Physiology ,Medicine and Health Sciences ,Intestinal Mucosa ,lcsh:Science ,Staining ,Innate Immune System ,Multidisciplinary ,Tight junction ,Cell Death ,Chemistry ,Interleukin-18 ,Cell Staining ,Cell biology ,Cytokine ,Cell Processes ,Medical Microbiology ,030220 oncology & carcinogenesis ,Viral Pathogens ,Physical Sciences ,Viruses ,Intercellular Signaling Peptides and Proteins ,Cytokines ,Interleukin 18 ,Female ,Anatomy ,Cellular Types ,Pathogens ,Junctional Complexes ,Research Article ,Cell Physiology ,Myosin light-chain kinase ,Immunology ,Materials Science ,Material Properties ,Research and Analysis Methods ,Microbiology ,Permeability ,Tight Junctions ,Adherens junction ,03 medical and health sciences ,Retroviruses ,medicine ,Humans ,Claudin ,Microbial Pathogens ,Intestinal permeability ,lcsh:R ,Lentivirus ,Organisms ,Biology and Life Sciences ,HIV ,Epithelial Cells ,Cell Biology ,Molecular Development ,medicine.disease ,Gastrointestinal Tract ,030104 developmental biology ,Biological Tissue ,Specimen Preparation and Treatment ,Bacterial Translocation ,Immune System ,HIV-1 ,lcsh:Q ,Caco-2 Cells ,Digestive System ,Developmental Biology - Abstract
Interleukin-18 (IL-18) is a pleiotropic cytokine of the IL-1 family with multiple context dependent functions. We and others have shown that HIV infection is accompanied by increased circulating levels of IL-18 along with decreased levels of its antagonist, Interleukin-18 Binding Protein (IL-18BP). The infection is also accompanied by intestinal inflammation and decreased intestinal integrity as measured by intestinal permeability, regeneration and repair. However, little is known concerning the relation between high level of IL-18 associated with the viral infection and intestinal permeability. Here we demonstrate that HIV treatment increases production of IL-18 and decreases that of IL-18BP production in human intestinal epithelial cell (IEC) lines. IL-18 causes apoptosis of the IEC by activating caspase-1 and caspase-3. It induces epithelial barrier hyperpermeability by decreasing and disrupting both tight and adherens junction proteins, occludin, claudin 2 and beta-catenin. Disorganization of F-actin was also observed in the IEC that were exposed to the cytokine. Moreover IL-18 decreases transepithelial electrical resistance (TEER) in Caco-2 and increases permeability in HT29 monolayers. The cells' treatment with IL-18 causes an increase in the expression of phosphorylated myosin II regulatory light-chain (p-MLC) and myosin light-chain kinase (MLCK), and a decrease in phosphorylated Signal Transducer and Activator of Transcription (p-STAT)-5. This increase in p-MLC is suppressed by a Rho-kinase (ROCK)-specific inhibitor. Interestingly, the levels of the cytokine correlate with those of LPS in the circulation in three different categories of HIV infected patients (HAART-naïve and HAART-treated HIV-infected individuals, and Elite controls) as well as in healthy controls. Collectively, these results suggest that the HIV-induced IL-18 plays a role in increased intestinal permeability and microbial translocation observed in HIV-infected individuals.
- Published
- 2017
37. Assessment of chloroquine as a modulator of immune activation to improve CD4 recovery in immune nonresponding HIV-infected patients receiving antiretroviral therapy
- Author
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M. Patel, Danuta Radzioch, Joel Singer, Jean-Pierre Routy, Ido P. Kema, Cynthia Kanagaratham, Norbert Gilmore, Mohammad-Ali Jenabian, Petronela Ancuta, and Jonathan B. Angel
- Subjects
Chemokine ,Myeloid ,biology ,business.industry ,Health Policy ,chemistry.chemical_compound ,Infectious Diseases ,medicine.anatomical_structure ,Immune system ,chemistry ,Interferon ,Chloroquine ,Immunology ,medicine ,biology.protein ,Pharmacology (medical) ,business ,Viral load ,Kynurenine ,CD8 ,medicine.drug - Abstract
Objectives Chloroquine (CQ), an anti-inflammatory drug, inhibits Toll-like receptor (TLR) signalling in plasmacytoid dendritic cells (pDCs) and may be beneficial for HIV-infected patients in whom immune activation persists despite effective antiretroviral therapy (ART). The effect of CQ on CD4 T-cell recovery and immune activation in immune nonresponding patients receiving successful ART was therefore studied. Methods Nineteen adults on ART with CD4 counts ≤ 350 cells/μL and undetectable viral load (VL) orally received CQ at 250 mg/day for 24 weeks. Side effects, CD4 and CD8 T-cell counts, VL, T-cell activation, pDC proportion and plasma inflammatory markers were assessed at baseline, at 24 weeks, and at 12 weeks after CQ discontinuation (clinicaltrial.org registration #NCT02004314). Results CQ was well tolerated and all patients maintained an undetectable VL. The absolute CD4 and CD8 T-cell counts and their percentages, the pDC proportion, T-cell activation, D-dimer and C-reactive protein (CRP) plasma levels and the kynurenine/tryptophan ratio did not change with CQ treatment. Among nine cytokines/chemokines measured, only levels of interferon (IFN)-α2 were significantly increased by CQ treatment. Conclusions CQ was well tolerated in patients with low CD4 T-cell counts despite long-term effective ART; however, 24 weeks of CQ treatment did not improved CD4 T-cell recovery, lymphoid and myeloid immune activation or inflammatory markers.
- Published
- 2014
38. Short Communication: Lower Baseline CD4 Count Is Associated with a Greater Propensity Toward Virological Failure in a Cohort of South African HIV Patients
- Author
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Paul Nijs, Alex Sigal, Doug Wilson, Cecilia T. Costiniuk, and Mohammad-Ali Jenabian
- Subjects
Adult ,Male ,medicine.medical_specialty ,Anti-HIV Agents ,Immunology ,HIV Infections ,Plasma viral load ,Cohort Studies ,South Africa ,Interquartile range ,Virology ,Internal medicine ,Chart review ,Humans ,Medicine ,Treatment Failure ,Retrospective Studies ,business.industry ,HIV ,Viral Load ,Virological failure ,CD4 Lymphocyte Count ,Surgery ,Regimen ,Infectious Diseases ,Cohort ,Hiv patients ,Female ,business - Abstract
The antiretroviral (ARV) service at Edendale Hospital in Pietermaritzburg, KwaZulu-Natal, South Africa has initiated more than 9,000 adults on therapy since 2004; however, virological outcomes among this patient cohort have not been systematically assessed. We conducted a retrospective chart review of patients initiating ARVs in recent years of the antiretroviral roll-out to determine the efficacy of this program. Clinic records were randomly selected for patients who had initiated ARVs between January 2009 and December 2012. Demographic and virological data were collected. Virological failure was defined as failure to achieve a plasma viral load (VL)25 copies/ml after 6-12 months of ARV initiation or ≥2 consecutive HIV-RNA VLs ≥400 copies/ml following suppression of25 copies/ml. Records for 228 individuals were reviewed. Twenty-one (9%) individuals experienced virological failure necessitating a regimen change. The median (interquartile range, IQR) duration of antiretroviral exposure was 19 (11-31) months. Individuals experiencing virological failure did not differ from individuals experiencing success with regards to sex, age, baseline hemoglobin, creatinine, alanine aminotransferase level, or weight (p0.05) except for having a lower baseline CD4 [median 74 (IQR 31-94) versus 142 (IQR 61-211) cells/μl; p=0.0036 (Mann-Whitney U test)]. No differences were observed between groups in type of ARV regimen, WHO stage at time of ARV initiation, or tuberculosis status. Therefore, using a relatively strict definition of virological failure, we observed that virological success was achievable in over 90% of individuals at the Edendale Hospital ARV clinic. Lower baseline CD4 was associated with greater propensity toward virological failure.
- Published
- 2014
39. Environmental and occupational exposures as predictors of airflow obstruction in an HIV tertiary care clinic
- Author
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Natale Wasef, Marina B. Klein, Christina De Castro, Donatella Wasef, Jason Szabo, Syim Salahuddin, Mohammad-Ali Jenabian, Zahra Saneei, Roy Nitulescu, Jean Bourbeau, Bertrand Lebouché, Joseph Cox, Cecilia T. Costiniuk, and Benjamin Smith
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Epidemiology ,business.industry ,Immunology ,Public Health, Environmental and Occupational Health ,Human immunodeficiency virus (HIV) ,Airflow obstruction ,medicine.disease_cause ,Tertiary care ,Microbiology ,QR1-502 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Infectious Diseases ,Virology ,Emergency medicine ,Medicine ,030212 general & internal medicine ,Public aspects of medicine ,RA1-1270 ,business - Published
- 2018
40. Identifying smoking cessation targets for people living with HIV and HIV-HCV
- Author
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Blake Linthewaite, Joseph Cox, Jason Szabo, Syim Salahuddin, Marie-Josée Brouillette, Jacques Fallu, Jean-Pierre Routy, Mohammad-Ali Jenabian, Hansi Peiris, Andreas Giannakis, Cecilia T. Costiniuk, Roger LeBlanc, Marina B. Klein, Bertrand Lebouché, and Sean Gilman
- Subjects
medicine.medical_specialty ,Epidemiology ,business.industry ,medicine.medical_treatment ,Immunology ,Public Health, Environmental and Occupational Health ,Human immunodeficiency virus (HIV) ,medicine.disease_cause ,Microbiology ,QR1-502 ,Infectious Diseases ,Virology ,Internal medicine ,medicine ,Smoking cessation ,Public aspects of medicine ,RA1-1270 ,business - Published
- 2018
41. The lungs as anatomical reservoirs of HIV infection
- Author
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Cecilia T. Costiniuk and Mohammad-Ali Jenabian
- Subjects
Disease reservoir ,Human immunodeficiency virus (HIV) ,virus diseases ,Biology ,medicine.disease ,medicine.disease_cause ,Antiretroviral therapy ,Virology ,Peripheral blood ,Virus ,Infectious Diseases ,Virus latency ,Immunology ,medicine - Abstract
Failure of antiretroviral therapy to eradicate HIV, even in individuals who suppress the virus to undetectable levels, is a consequence of persistent infection in latently infected cells and within anatomical reservoirs. Support for the notion that the lungs are distinct anatomical reservoirs of HIV comes from a spectrum of studies that have documented different levels of HIV within the lungs compared with the peripheral blood. Different HIV variants have also been found within these two compartments, including variants with distinct antiretroviral resistance mutations. Given that macrophages are long-lived cellular reservoirs of HIV because of their resistance to apoptosis, HIV can persist for prolonged periods within alveolar macrophages that are abundant within the lungs. Furthermore, the large number of cells in close proximity within the lungs provides fertile grounds for cell-to-cell spread of HIV. Distinct immunological pressures in the lungs compared with the peripheral blood likely account for differences in HIV levels within these two compartments in addition to the finding of different variants within these regions. Furthermore, coinfections and tobacco may serve as local stimuli to induce further HIV replication within the lungs. Herein, we review the evidence supporting the notion that lungs are important reservoirs of HIV infection, and we discuss various factors influencing HIV burden within these reservoirs.
- Published
- 2013
42. Understanding Factors That Modulate HIV Infection at the Female Genital Tract Mucosae for the Rationale Design of Microbicides
- Author
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Héla Saïdi, Mohammad-Ali Jenabian, and Laurent Bélec
- Subjects
Male ,Female circumcision ,Chemokine ,Receptors, CCR5 ,Immunology ,Human immunodeficiency virus (HIV) ,HIV Infections ,Virus Replication ,medicine.disease_cause ,Complement components ,Anti-Infective Agents ,Semen ,Virology ,Microbicide ,medicine ,Animals ,Humans ,Immunity, Mucosal ,Opsonin ,biology ,Epithelial Cells ,Immunity, Innate ,Virus Shedding ,Microbicides for sexually transmitted diseases ,Infectious Diseases ,Immunological Factors ,Drug Design ,Vagina ,biology.protein ,Macaca ,Female - Abstract
Women are now becoming the pivot of the epidemiological spread of HIV infection worldwide, especially in developing countries. Therefore, research to develop an efficient microbicide is now a priority for the prevention of HIV-1 acquisition in exposed women. However, recent disappointing failures in microbicide clinical trials revealed major gaps in basic and applied knowledge that hinder the development of effective microbicide formulations. Indeed, the inhibitory power of microbicide molecules may be affected by several physiological and immunological factors present in male and female genital tracts. Furthermore, mucosal crossing of HIV-1 to increase the ability to reach the submucosal target cells (macrophages, lymphocytes, and dendritic cells) may be modulated by supraepithelial factors such as seminal complement components (opsonized HIV-1), by epithelial factors released in the submucosal microenvironment such as antimicrobial soluble factors, cytokines, and chemokines, and by potent intraepithelial and submucosal innate immunity. The design of vaginal microbicide formulations should take into account an understanding of the intimate mechanisms involved in the crossing of HIV through the female genital mucosae, in the context of a mixture of both male and female genital fluids.
- Published
- 2012
43. Immune tolerance properties of the testicular tissue as a viral sanctuary site in ART-treated HIV-infected adults
- Author
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Maud Bélanger, Petronela Ancuta, Mohammad-Ali Jenabian, Vikram Mehraj, Rémi Fromentin, Feras M. Ghazawi, Jean-Pierre Routy, Reina Bendayan, Nicolas Chomont, Joëlle Brousseau, Cecilia T. Costiniuk, and Pierre Brassard
- Subjects
0301 basic medicine ,Adult ,Male ,Immunology ,HIV Infections ,Human leukocyte antigen ,CD38 ,Biology ,Peripheral blood mononuclear cell ,Interstitial cell ,Article ,Immune tolerance ,03 medical and health sciences ,chemistry.chemical_compound ,Antigen ,T-Lymphocyte Subsets ,Testis ,Immune Tolerance ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Immunologic Factors ,Gene Expression Profiling ,030104 developmental biology ,Infectious Diseases ,chemistry ,Anti-Retroviral Agents ,DNA, Viral ,Kynurenine - Abstract
Objective HIV persistence in long-lived infected cells and in anatomical sanctuary sites are major hurdles to HIV eradication. Testicular tissue may represent a significant viral sanctuary site as it constitutes an immunologically privileged compartment. We assessed immunotolerance properties of the testicular tissue in individuals receiving suppressive antiretroviral therapy (ART). Design and methods Testicular tissue and matched blood samples were collected from six virally suppressed adults and 10 HIV-uninfected controls prior to sex reassignment surgery. T cells were purified from freshly isolated testicular interstitial cell suspensions. T-cell subsets, expression of immune activation markers and HIV DNA were assessed in matched testicular cells and peripheral blood mononuclear cells (PBMCs). Results When compared with PBMCs, testes were characterized by a lower CD4 T-cell proportion among total T cells, a decrease in the frequency of naive cells, an increase in the frequency of effector-memory T cells and an increase in CCR5 expression in both the HIV+ and HIV- groups. In HIV-infected individuals on ART, testes displayed higher T-cell immune activation (Coexpression of CD38 and Human Leukocyte Antigen - antigen D Related) than PBMCs. In both groups, testes were characterized by higher frequencies of immunosuppressive CD39 regulatory T cells and a massive increase in CD73 expression on CD8 T cells. In addition, a remarkable increase in indoleamine-pyrrole 2,3-dioxygenase immunosuppressive enzyme involved in tryptophan/kynurenine catabolism was observed in testes versus blood. Rare cells harboring HIV DNA were detected in testes from five out six participants. Conclusion These findings suggest that the adenosine and tryptophan/kynurenine immune-metabolic pathways contribute to immune tolerance in testicular tissue. Our results suggest that testes may represent a distinctive HIV sanctuary site during ART.
- Published
- 2016
44. New insights into the heterogeneity of Th17 subsets contributing to HIV-1 persistence during antiretroviral therapy
- Author
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Annie Gosselin, Jean-Philippe Goulet, Steven G. Deeks, Mohammad-Ali Jenabian, Shant M. Vartanian, Hugo Soudeyns, Jean-Pierre Routy, Nicolas Chomont, Rémi Fromentin, Vanessa Sue Wacleche, Patricia Monteiro, and Petronela Ancuta
- Subjects
0301 basic medicine ,Human immunodeficiency virus (HIV) ,HIV Infections ,C-C chemokine receptor type 6 ,medicine.disease_cause ,CXCR3 ,Virus Replication ,Persistence (computer science) ,Antiretroviral Therapy, Highly Active ,Receptors ,2.1 Biological and endogenous factors ,Longitudinal Studies ,Aetiology ,hemic and immune systems ,3. Good health ,Infectious Diseases ,HIV/AIDS ,Th17 ,Antibody ,Infection ,ART ,Microbial translocation ,Human ,Receptors, CCR6 ,Receptors, CCR4 ,Receptors, CXCR3 ,Clinical Sciences ,HIV reservoirs ,Antiretroviral Therapy ,chemical and pharmacologic phenomena ,Biology ,03 medical and health sciences ,Virology ,medicine ,Humans ,Highly Active ,Permissive ,Prevention ,Research ,Antiretroviral therapy ,030104 developmental biology ,Cross-Sectional Studies ,Immunology ,biology.protein ,HIV-1 ,Th17 Cells ,CCR4 ,CCR6 ,Immunologic Memory - Abstract
Background Th17 cells are permissive to HIV-1 infection and their depletion from the gut of infected individuals leads to microbial translocation, a major cause for non-AIDS co-morbidities. Most recent evidence supports the contribution of long-lived Th17 cells to HIV persistence during antiretroviral therapy (ART). However, the identity of long-lived Th17 cells remains unknown. Results Here, we performed an in-depth transcriptional and functional characterization of four distinct Th17 subsets and investigated their contribution to HIV reservoir persistence during ART. In addition to the previously characterized CCR6+CCR4+ (Th17) and CCR6+CXCR3+ (Th1Th17) subsets, we reveal the existence of two novel CCR6+ subsets, lacking (double negative, CCR6+DN) or co-expressing CXCR3 and CCR4 (double positive, CCR6+DP). The four subsets shared multiple Th17-polarization markers, a fraction of cells proliferated in response to C. albicans, and exhibited lineage commitment and plasticity when cultured under Th17 and Th1 conditions, respectively. Of note, fractions of CCR6+DN and Th17 demonstrated stable Th17-lineage commitment under Th1-polarization conditions. Among the four subsets, CCR6+DN expressed a unique transcriptional signature indicative of early Th17 development (IL-17F, STAT3), lymph-node homing (CCR7, CD62L), follicular help (CXCR5, BCL6, ASCL2), and self-renewal (LEFI, MYC, TERC). Cross sectional and longitudinal studies demonstrated that CCR6+DN cells were the most predominant CCR6+ subset in the blood before and after ART initiation; high frequencies of these cells were similarly observed in inguinal lymph nodes of individuals receiving long-term ART. Importantly, replication competent HIV was isolated from CCR6+DN of ART-treated individuals. Conclusions Together, these results provide new insights into the functional heterogeneity of Th17-polarized CCR6+CD4+ T-cells and support the major contribution of CCR6+DN cells to HIV persistence during ART. Electronic supplementary material The online version of this article (doi:10.1186/s12977-016-0293-6) contains supplementary material, which is available to authorized users.
- Published
- 2016
45. Influence of microbial translocation and inflammation on CD8 T-cell elevation in primary HIV-1 infection
- Author
-
Cécile Tremblay, Réjean Thomas, Jean-Pierre Routy, Vikram Mehraj, Mohammad-Ali Jenabian, Rosalie Ponte, Roger LeBlanc, Bertrand Lebouché, and Jean-Guy Baril
- Subjects
Epidemiology ,Immunology ,Public Health, Environmental and Occupational Health ,Human immunodeficiency virus (HIV) ,Elevation ,Inflammation ,Biology ,medicine.disease_cause ,Microbiology ,QR1-502 ,Infectious Diseases ,Virology ,medicine ,Cytotoxic T cell ,medicine.symptom ,Public aspects of medicine ,RA1-1270 ,Microbial translocation - Published
- 2016
46. Current topics in HIV pathogenesis, part 2: Inflammation drives a Warburg-like effect on the metabolism of HIV-infected subjects
- Author
-
Vikram Mehraj, Mouna Aounallah, Xavier Dagenais-Lussier, Jean-Pierre Routy, Mohammad-Ali Jenabian, Mohamed El-Far, Julien van Grevenynghe, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), McGill University Health Center [Montreal] (MUHC), Département des Sciences Biologiques [Montréal], and Université du Québec à Montréal = University of Québec in Montréal (UQAM)
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Endocrinology, Diabetes and Metabolism ,[SDV]Life Sciences [q-bio] ,Immunology ,Antigen presentation ,Inflammation ,Context (language use) ,HIV Infections ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Autoimmunity ,Inflammasome ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,Humans ,Innate immunity ,Innate immune system ,Immunity, Innate ,030104 developmental biology ,Metabolism ,030220 oncology & carcinogenesis ,Quality of Life ,HIV-1 ,medicine.symptom ,medicine.drug - Abstract
International audience; HIV-1 infection leads to a depletion of CD4 T-cells associated with a persistent immune inflammation and changes in cellular metabolism. Most effort of managing HIV infection with combination of antiretroviral therapies (ART) has been focused on CD4 T-cell recovery, while control of persistent immune inflammation and metabolism were relatively underappreciated in the past. Recent discoveries on the interplay between innate immunity, inflammation (especially the inflammasome) and metabolic changes in the context of cancer and autoimmunity provide an emerging field for chronic viral infections including HIV-1. In a previous review, we described the deregulated metabolism contributing to immune dysfunctions such as alteration of memory T-cell responses, mucosal protection, and dendritic cell-related antigen presentation. Here, we summarize the latest knowledge on the detrimental influence of long-lasting inflammation and inflammasome activation induced by HIV-1, gut dysbiosis, and bacterial translocation, on metabolism during the course of viral infection. We also report on the inability of ART to fully counteract inflammation, resulting in partial metabolic improvement and leading to an insufficient decrease in the risk of non-AIDS events. Further advances in our understanding of the relationship between inflammation, altered metabolism, and long-term ART is warranted. Additionally, there is a critical need for developing new strategies to regulate the pro-inflammatory signals to enhance cellular metabolism and immune functions in order to improve the quality of life of individuals living with HIV-1.
- Published
- 2016
47. Role of drug transporters and metabolic enzymes in antiretroviral drug (ARV) disposition in testicular tissue: potential contribution to HIV-1 persistence
- Author
-
N. Sheehan, T. Hoque, S.K. Whyte, Kishanda Vyboh, M. Belanger, Jean-Pierre Routy, Courtney V. Fletcher, R. Bendayan, Y. Huang, Nicolas Chomont, P. Brassard, and Mohammad-Ali Jenabian
- Subjects
Drug ,Testicular tissue ,Epidemiology ,business.industry ,media_common.quotation_subject ,Immunology ,Public Health, Environmental and Occupational Health ,Human immunodeficiency virus (HIV) ,Transporter ,Antiretroviral drug ,Disposition ,Pharmacology ,medicine.disease_cause ,Microbiology ,QR1-502 ,Persistence (computer science) ,Infectious Diseases ,Metabolic enzymes ,Virology ,medicine ,Public aspects of medicine ,RA1-1270 ,business ,media_common - Published
- 2015
48. The transcriptional program governed by RORγt favors HIV-1 replication in CCR4+CCR6+ Th17 cells
- Author
-
Y. Zhang, Elias K. Haddad, J.P. Goulet, V.S. Wacleche, Rafick Pierre Sekaly, Jean-Pierre Routy, Cécile Tremblay, Mohammad-Ali Jenabian, J. Niessl, A. Cleret-Buhot, N. Chomont, Petronela Ancuta, M. El-Far, P. Monteiro, A. Gosselin, and D. Planas
- Subjects
Epidemiology ,Immunology ,Public Health, Environmental and Occupational Health ,Human immunodeficiency virus (HIV) ,CCR4 ,C-C chemokine receptor type 6 ,Biology ,medicine.disease_cause ,Virology ,Microbiology ,QR1-502 ,Infectious Diseases ,RAR-related orphan receptor gamma ,Replication (statistics) ,medicine ,Public aspects of medicine ,RA1-1270 - Published
- 2015
49. Identification of novel HIV-1 dependency factors in primary CCR4+CCR6+Th17 cells via a genome-wide transcriptional approach
- Author
-
Cécile Tremblay, Mohammad-Ali Jenabian, Jean-Pierre Routy, Yuwei Zhang, Vanessa Sue Wacleche, Aurélie Cleret-Buhot, Delphine Planas, Jean Philippe Goulet, Petronela Ancuta, Annie Gosselin, Patricia Monteiro, Mohamed El-Far, Elias K. Haddad, Rafick Pierre Sekaly, and Nicolas Chomont
- Subjects
Male ,Permissiveness ,Protein Tyrosine Phosphatase, Non-Receptor Type 13 ,HIV Infections ,Virus Replication ,PTPN13 ,NF-κB ,Transcriptome ,0302 clinical medicine ,T-Lymphocyte Subsets ,RNA interference ,Cells, Cultured ,0303 health sciences ,NF-kappa B ,hemic and immune systems ,3. Good health ,Cell biology ,Infectious Diseases ,medicine.anatomical_structure ,Female ,RNA Interference ,MAP3K4 ,TCR ,Adult ,Receptors, CCR6 ,Receptors, CCR4 ,CD96 ,T cell ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,Biology ,MAP Kinase Kinase Kinase 4 ,03 medical and health sciences ,Virology ,medicine ,Humans ,Immunity, Mucosal ,030304 developmental biology ,Research ,Gene Expression Profiling ,T-cell receptor ,HIV-1 dependency factors ,Th1 Cells ,Gene expression profiling ,Viral replication ,Immunology ,HIV-1 ,Th17 Cells ,Immunologic Memory ,Human Th17 cells ,030215 immunology - Abstract
Background The HIV-1 infection is characterized by profound CD4+ T cell destruction and a marked Th17 dysfunction at the mucosal level. Viral suppressive antiretroviral therapy restores Th1 but not Th17 cells. Although several key HIV dependency factors (HDF) were identified in the past years via genome-wide siRNA screens in cell lines, molecular determinants of HIV permissiveness in primary Th17 cells remain to be elucidated. Results In an effort to orient Th17-targeted reconstitution strategies, we investigated molecular mechanisms of HIV permissiveness in Th17 cells. Genome-wide transcriptional profiling in memory CD4+ T-cell subsets enriched in cells exhibiting Th17 (CCR4+CCR6+), Th1 (CXCR3+CCR6−), Th2 (CCR4+CCR6−), and Th1Th17 (CXCR3+CCR6+) features revealed remarkable transcriptional differences between Th17 and Th1 subsets. The HIV-DNA integration was superior in Th17 versus Th1 upon exposure to both wild-type and VSV-G-pseudotyped HIV; this indicates that post-entry mechanisms contribute to viral replication in Th17. Transcripts significantly enriched in Th17 versus Th1 were previously associated with the regulation of TCR signaling (ZAP-70, Lck, and CD96) and Th17 polarization (RORγt, ARNTL, PTPN13, and RUNX1). A meta-analysis using the NCBI HIV Interaction Database revealed a set of Th17-specific HIV dependency factors (HDFs): PARG, PAK2, KLF2, ITGB7, PTEN, ATG16L1, Alix/AIP1/PDCD6IP, LGALS3, JAK1, TRIM8, MALT1, FOXO3, ARNTL/BMAL1, ABCB1/MDR1, TNFSF13B/BAFF, and CDKN1B. Functional studies demonstrated an increased ability of Th17 versus Th1 cells to respond to TCR triggering in terms of NF-κB nuclear translocation/DNA-binding activity and proliferation. Finally, RNA interference studies identified MAP3K4 and PTPN13 as two novel Th17-specific HDFs. Conclusions The transcriptional program of Th17 cells includes molecules regulating HIV replication at multiple post-entry steps that may represent potential targets for novel therapies aimed at protecting Th17 cells from infection and subsequent depletion in HIV-infected subjects. Electronic supplementary material The online version of this article (doi:10.1186/s12977-015-0226-9) contains supplementary material, which is available to authorized users.
- Published
- 2015
50. Imbalanced production of IL-18 and its antagonist in human diseases, and its implications for HIV-1 infection
- Author
-
Devendra Amre, Cécile Tremblay, Ossama Allam, Zainab Aldabah, Mohammad-Ali Jenabian, Patrick Sagala, Ali Ahmad, Jean-Pierre Routy, Suzanne Samarani, and Vikram Mehraj
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Immunology ,Caspase 1 ,Biochemistry ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Immunology and Allergy ,Humans ,Molecular Biology ,Caspase ,Acquired Immunodeficiency Syndrome ,biology ,Antagonist ,Interleukin-18 ,Inflammasome ,Hematology ,P2RX7 ,030104 developmental biology ,Cytokine ,030220 oncology & carcinogenesis ,biology.protein ,HIV-1 ,Intercellular Signaling Peptides and Proteins ,Interleukin 18 ,medicine.drug - Abstract
IL-18 is a pleiotropic and multifunctional cytokine that belongs to the IL-1 family. It is produced as a biologically inactive precursor, which is cleaved into its active mature form mainly by caspase-1. The caspase becomes active from its inactive precursor (procaspase-1) upon assembly of an inflammasome. Because of IL-18's potential pro-inflammatory and tissue destructive effects, its biological activities are tightly controlled in the body by its naturally occurring antagonist called IL-18BP. The antagonist is produced in the body both constitutively and in response to an increased production of IL-18 as a negative feedback mechanism. Under physiological conditions, most of IL-18 in the circulation is bound with IL-18BP and is inactive. However, an imbalance in the production of IL-18 and its antagonist (an increase in the production of IL-18 with a decrease, no increase or an insufficient increase in the production of IL-18BP) has been described in many chronic inflammatory diseases in humans. The imbalance results in an increase in the concentrations of free IL-18 (unbound with its antagonist) resulting in increased biological activities of the cytokine that contribute towards pathogenesis of the disease. In this article, we provide an overview of the current biology of IL-18 and its antagonist, discuss how the imbalance occurs in HIV infections and how it contributes towards development of AIDS and other non-AIDS-associated clinical conditions occurring in HIV-infected individuals undergoing combination anti-retroviral therapy (cART). Finally, we discuss challenges facing immunotherapeutic strategies aimed at restoring balance between IL-18 and its antagonist in these patients.
- Published
- 2015
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