21 results on '"Laura Tarancon-Diez"'
Search Results
2. Long-term evolution in liver disease markers and immune and lipid profiles in vertically HIV/HCV-coinfected youths with sustained viral response after direct-acting antivirals therapy
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Laura Tarancon-Diez, Itzíar Carrasco, Santiago Jiménez de Ory, Arantxa Berzosa Sánchez, Alicia Hernanz-Lobo, Marta Montero-Alonso, Montserrat Laguno, Jose I. Bernardino, Luis López-Cortés, Teresa Aldamiz-Echevarría, Pilar Collado, Otilia Bisbal, Gloria Samperiz, César Gavilán, Mª José Ríos, Sofía Ibarra, María Luisa Navarro, and Mª Ángeles Muñoz-Fernández
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Direct-acting antivirals ,Vertically acquired HIV/HCV-coinfection ,Hepatic profile ,Immune profile ,Lipid profile ,Therapeutics. Pharmacology ,RM1-950 - Abstract
This study aimed to analyse the long-term effect of direct-acting antivirals (DAAs) in vertically acquired HIV/HCV-coinfected youths. We performed a multicentre, longitudinal and observational study within the Spanish Cohort of HIV-infected children and adolescents and vertically HIV-infected patients transferred to Adult Units (CoRISpe-FARO). We included HIV/HCV-coinfected youths (n = 24) that received DAAs between 2015 and 2017 with successful sustained viral response (SVR) with a subsequent follow-up of at least three years. Long-term evolution in liver disease severity and haematologic markers, lipid and immune profiles after SVR were assessed. Study times were the start date of DAAs treatment (baseline, T0) and 1, 2, 3, 4 and 5 years after SVR (T1, T2, T3, T4 and T5, respectively). We observed global improvements in liver function data that persist over time and a favourable haematologic and immune outcome at the long-term including a constant augment in leucocytes, neutrophils, neutrophils to lymphocytes ratio (NLR) and CD4/CD8 ratio over-time. Regarding the lipid profile, we found a significant increase in total cholesterol T2, total cholesterol/high-density lipoprotein (HDL) ratio at T4, triglycerides at T5, low-density lipoprotein (LDL) over time, and a decrease in HDL in all patients but with marked higher levels in the subgroup receiving anti-HIV Protease Inhibitor (PI)-based regimens. Comparisons of vertically HIV/HCV-coinfected youths after SVR at 3-year follow-up and a control group of vertically HIV-monoinfected youths never infected by HCV showed no significant differences in most variables analysed, suggesting a possible normalization in all parameters.
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- 2023
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3. Toll-like receptor agonists enhance HIV-specific T cell response mediated by plasmacytoid dendritic cells in diverse HIV-1 disease progression phenotypesResearch in context
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Maria R. Jimenez-Leon, Carmen Gasca-Capote, Laura Tarancon-Diez, Beatriz Dominguez-Molina, Macarena Lopez-Verdugo, Ryan Ritraj, Isabel Gallego, Ana I. Alvarez-Rios, Joana Vitalle, Sara Bachiller, María Inés Camacho-Sojo, Alberto Perez-Gomez, Nuria Espinosa, Cristina Roca-Oporto, Mohamed Rafii-El-Idrissi Benhnia, Alicia Gutierrez-Valencia, Luis F. Lopez-Cortes, and Ezequiel Ruiz-Mateos
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Plasmacytoid dendritic cells ,TLR agonists ,HIV-Infection ,HIV-1 restriction factors and immunotherapy ,Medicine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Plasmacytoid dendritic cells (pDCs) sense viral and bacterial products through Toll-like receptor (TLR)-7 and -9 and translate this sensing into Interferon-α (IFN-α) production and T-cell activation. The understanding of the mechanisms involved in pDCs stimulation may contribute to HIV-cure immunotherapeutic strategies. The objective of the present study was to characterize the immunomodulatory effects of TLR agonist stimulations in several HIV-1 disease progression phenotypes and in non HIV-1 infected donors. Methods: pDCs, CD4 and CD8 T-cells were isolated from 450 ml of whole blood from non HIV-1 infected donors, immune responders (IR), immune non responders (INR), viremic (VIR) and elite controller (EC) participants. pDCs were stimulated overnight with AT-2, CpG-A, CpG-C and GS-9620 or no stimuli. After that, pDCs were co-cultured with autologous CD4 or CD8 T-cells and with/without HIV-1 (Gag peptide pool) or SEB (Staphylococcal Enterotoxin B). Cytokine array, gene expression and deep immunophenotyping were assayed. Findings: pDCs showed an increase of activation markers levels, interferon related genes, HIV-1 restriction factors and cytokines levels after TLR stimulation in the different HIV-disease progression phenotypes. This pDC activation was prominent with CpG-C and GS-9620 and induced an increase of HIV-specific T-cell response even in VIR and INR comparable with EC. This HIV-1 specific T-cell response was associated with the upregulation of HIV-1 restriction factors and IFN-α production by pDC. Interpretation: These results shed light on the mechanisms associated with TLR-specific pDCs stimulation associated with the induction of a T-cell mediated antiviral response which is essential for HIV-1 eradication strategies. Funding: This work was supported by Gilead fellowship program, the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, FEDER, “a way to make Europe”) and the Red Temática de Investigación Cooperativa en SIDA and by the Spanish National Research Council (CSIC).
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- 2023
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4. Immunoescape of HIV-1 in Env-EL9 CD8 + T cell response restricted by HLA-B*14:02 in a Non progressor who lost twenty-seven years of HIV-1 control
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Ana Moyano, Oscar Blanch-Lombarte, Laura Tarancon-Diez, Nuria Pedreño-Lopez, Miguel Arenas, Tamara Alvaro, Concepción Casado, Isabel Olivares, Mar Vera, Carmen Rodriguez, Jorge del Romero, Cecilio López-Galíndez, Ezequiel Ruiz-Mateos, Julia G. Prado, and María Pernas
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Long-term non-progressor (LTNP) ,Loss of viral control (LVC) ,Env-EL9 escape HLA-B*14:02 ,CD8 + T-cells ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background Long-Term Non-Progressors (LTNPs) are untreated Human Immunodeficiency virus type 1 (HIV-1) infected individuals able to control disease progression for prolonged periods. However, the LTNPs status is temporary, as viral load increases followed by decreases in CD4 + T-cell counts. Control of HIV-1 infection in LTNPs viremic controllers, have been associated with effective immunodominant HIV-1 Gag-CD8 + T-cell responses restricted by protective HLA-B alleles. Individuals carrying HLA-B*14:02 control HIV-1 infection is related to an immunodominant Env-CD8 + T-cell response. Limited data are available on the contribution of HLA-B*14:02 CD8 + T -cells in LTNPs. Results In this study, we performed a virological and immunological detailed analysis of an HLA-B*14:02 LNTP individual that lost viral control (LVC) 27 years after HIV-1 diagnosis. We analysed viral evolution and immune escape in HLA-B*14:02 restricted CD8 + T -cell epitopes and identified viral evolution at the Env-EL9 epitope selecting the L592R mutation. By IFN-γ ELISpot and immune phenotype, we characterized HLA- B*14:02 HIV-1 CD8 + T cell responses targeting, Gag-DA9 and Env-EL9 epitopes before and after LVC. We observed an immunodominant response against the Env-EL9 epitope and a decreased of the CD8 T + cell response over time with LVC. Loss of Env-EL9 responses was concomitant with selecting K588R + L592R mutations at Env-EL9. Finally, we evaluated the impact of Env-EL9 escape mutations on HIV-1 infectivity and Env protein structure. The K588R + L592R escape variant was directly related to HIV-1 increase replicative capacity and stability of Env at the LVC. Conclusions These findings support the contribution of immunodominant Env-EL9 CD8 + T-cell responses and the imposition of immune escape variants with higher replicative capacity associated with LVC in this LNTP. These data highlight the importance of Env-EL9 specific-CD8 + T-cell responses restricted by the HLA-B*14:02 and brings new insights into understanding long-term HIV-1 control mediated by Env mediated CD8 + T-cell responses.
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- 2022
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5. SARS-CoV2 Infection During Pregnancy Causes Persistent Immune Abnormalities in Women Without Affecting the Newborns
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Elena Vazquez-Alejo, Laura Tarancon-Diez, Itzíar Carrasco, Sara Vigil-Vázquez, Mar Muñoz-Chapuli, Elena Rincón-López, Jesús Saavedra-Lozano, Mar Santos-Sebastián, David Aguilera-Alonso, Alicia Hernanz-Lobo, Begoña Santiago-García, Juan Antonio de León-Luis, Patricia Muñoz, Manuel Sánchez-Luna, María Luisa Navarro, and Mª Ángeles Muñoz-Fernández
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SARS-CoV2 ,pregnancy ,SARS-CoV2 exposed newborns ,immune system ,longitudinal analysis ,Immunologic diseases. Allergy ,RC581-607 - Abstract
SARS-CoV2 infection in pregnancy and exposed newborns is poorly known. We performed a longitudinal analysis of immune system and determined soluble cytokine levels in pregnant women infected with SARS-CoV2 and in their newborns. Women with confirmed SARS-CoV2 infection and their exposed uninfected newborns were recruited from Hospital General Universitario Gregorio Marañón. Peripheral blood mononuclear cells (PBMCs), cord cells and plasma were collected at birth and 6 months later. Immunophenotyping of natural killer (NK), monocytes and CD4/CD8 T-cells were studied in cryopreserved PBMCs and cord cells by multiparametric flow cytometry. Up to 4 soluble pro/anti-inflammatory cytokines were assessed in plasma/cord plasma by ELISA assay. SARS-CoV2-infected mothers and their newborns were compared to matched healthy non-SARS-CoV2-infected mothers and their newborns. The TNFα and IL-10 levels of infected mothers were higher at baseline than those of healthy controls. Infected mothers showed increased NK cells activation and reduced expression of maturation markers that reverted after 6 months. They also had high levels of Central Memory and low Effector Memory CD4-T cell subsets. Additionally, the increased CD4- and CD8-T cell activation (CD154 and CD38) and exhaustion (TIM3/TIGIT) levels at baseline compared to controls remained elevated after 6 months. Regarding Treg cells, the levels were lower at infected mothers at baseline but reverted after 6 months. No newborn was infected at birth. The lower levels of monocytes, NK and CD4-T cells observed at SARS-CoV2-exposed newborns compared to unexposed controls significantly increased 6 months later. In conclusion, SARS-CoV2 infection during pregnancy shows differences in immunological components that could lead newborns to future clinical implications after birth. However, SARS-CoV2 exposed 6-months-old newborns showed no immune misbalance, whereas the infected mothers maintain increased activation and exhaustion levels in T-cells after 6 months.
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- 2022
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6. Persistent Exhausted T-Cell Immunity after Severe COVID-19: 6-Month Evaluation in a Prospective Observational Study
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Elena Vazquez-Alejo, Laura Tarancon-Diez, Maria de la Sierra Espinar-Buitrago, Miguel Genebat, Alba Calderón, Guillermo Pérez-Cabeza, Esmeralda Magro-Lopez, Manuel Leal, and Mª Ángeles Muñoz-Fernández
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SARS-CoV-2 ,severe COVID-19 ,hospitalization ,immune exhaustion profile ,SARS-CoV-2-specific T-cell response ,long-term evolution ,Medicine - Abstract
Introduction: Severe COVID-19 can result in a significant and irreversible impact on long-term recovery and subsequent immune protection. Understanding the complex immune reactions may be useful for establishing clinically relevant monitoring. Methods: Hospitalized adults with SARS-CoV-2 between March/October 2020 (n = 64) were selected. Cryopreserved peripheral blood mononuclear cells (PBMCs) and plasma samples were obtained at hospitalization (baseline) and 6 months after recovery. Immunological components’ phenotyping and SARS-CoV-2-specific T-cell response were studied in PBMCs by flow cytometry. Up to 25 plasma pro/anti-inflammatory cytokines/chemokines were assessed by LEGENDplex immunoassays. The SARS-CoV-2 group was compared to matched healthy donors. Results: Biochemical altered parameters during infection were normalized at a follow-up time point in the SARS-CoV-2 group. Most of the cytokine/chemokine levels were increased at baseline in the SARS-CoV-2 group. This group showed increased Natural Killer cells (NK) activation and decreased CD16high NK subset, which normalized six months later. They also presented a higher intermediate and patrolling monocyte proportion at baseline. T cells showed an increased terminally differentiated (TemRA) and effector memory (EM) subsets distribution in the SARS-CoV-2 group at baseline and continued to increase six months later. Interestingly, T-cell activation (CD38) in this group decreased at the follow-up time point, contrary to exhaustion markers (TIM3/PD1). In addition, we observed the highest SARS-CoV-2-specific T-cell magnitude response in TemRA CD4 T-cell and EM CD8 T-cell subsets at the six-months time point. Conclusions: The immunological activation in the SARS-CoV-2 group during hospitalization is reversed at the follow-up time point. However, the marked exhaustion pattern remains over time. This dysregulation could constitute a risk factor for reinfection and the development of other pathologies. Additionally, high SARS-CoV-2-specific T-cells response levels appear to be associated with infection severity.
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- 2023
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7. miRNA Profile Based on ART Delay in Vertically Infected HIV-1 Youths Is Associated With Inflammatory Biomarkers and Activation and Maturation Immune Levels
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Laura Tarancon-Diez, Irene Consuegra, Elena Vazquez-Alejo, Ricardo Ramos-Ruiz, José Tomás Ramos, María Luisa Navarro, and Mª Ángeles Muñoz-Fernández
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miRNA profile ,vertically acquired-HIV-1 infection ,ART ,youths ,inflammatory profile ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Early antiretroviral treatment (ART) in vertically acquired HIV-1-infection is associated with a rapid viral suppression, small HIV-1 reservoir, reduced morbimortality and preserved immune functions. We investigated the miRNA profile from vertically acquired HIV-1-infected young adults based on ART initiation delay and its association with the immune system activation. Using a microRNA panel and multiparametric flow cytometry, miRNome profile obtained from peripheral blood mononuclear cells and its association with adaptive and innate immune components were studied on vertically HIV-1-infected young adults who started ART early (EARLY, 0-53 weeks after birth) and later (LATE, 120-300 weeks). miR-1248 and miR-155-5p, were significantly upregulated in EARLY group compared with LATE group, while miR-501-3p, miR-548d-5p, miR-18a-3p and miR-296-5p were significantly downregulated in EARLY treated group of patients. Strong correlations were obtained between miRNAs levels and soluble biochemical biomarkers and immunological parameters including CD4 T-cell count and maturation by CD69 expression on CD4 T-cells and activation by HLA-DR on CD16high NK cell subsets for miR-1248 and miR-155-5p. In this preliminary study, a distinct miRNA signature discriminates early treated HIV-1-infected young adults. The role of those miRNAs target genes in the modulation of HIV-1 replication and latency may reveal new host signaling pathways that could be manipulated in antiviral strategies. Correlations between miRNAs levels and inflammatory and immunological markers highlight those miRNAs as potential biomarkers for immune inflammation and activation in HIV-1-infected young adults who initiated a late ART.
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- 2022
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8. Permanent control of HIV-1 pathogenesis in exceptional elite controllers: a model of spontaneous cure
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Concepcion Casado, Cristina Galvez, Maria Pernas, Laura Tarancon-Diez, Carmen Rodriguez, Víctor Sanchez-Merino, Mar Vera, Isabel Olivares, Rebeca De Pablo-Bernal, Alberto Merino-Mansilla, Jorge Del Romero, Ramon Lorenzo-Redondo, Ezequiel Ruiz-Mateos, María Salgado, Javier Martinez-Picado, and Cecilio Lopez-Galindez
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Medicine ,Science - Abstract
Abstract Elite controllers (EC) represent a small subset of HIV-1-infected people that spontaneously control viral replication. However, natural virological suppression and absence of immune dysfunction are not always long-term sustained. We define exceptional EC (EEC) as HIV-1 subjects who maintain the EC characteristics without disease progression for more than 25 years. We analyzed three EEC, diagnosed between 1988 and 1992, who never showed signs of clinical disease progression in absence of any antiretroviral treatment. A comprehensive clinical, virological, and immunological study was performed. The individuals simultaneously exhibited ≥3 described host protective alleles, low levels of total HIV-1 DNA (0.50). Inflammation levels of EEC were similar to HIV-1 negative donors. Remarkably, they showed an exceptional lack of viral evolution and 8-fold lower genetic diversity (
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- 2020
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9. Threshold Ferritin Concentrations Reflecting Early Iron Deficiency Based on Hepcidin and Soluble Transferrin Receptor Serum Levels in Patients with Absolute Iron Deficiency
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Laura Tarancon-Diez, Miguel Genebat, Manuela Roman-Enry, Elena Vázquez-Alejo, Maria de la Sierra Espinar-Buitrago, Manuel Leal, and Mª Ángeles Muñoz-Fernandez
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ferritin ,iron deficiency ,hepcidin ,soluble transferrin receptor ,Nutrition. Foods and food supply ,TX341-641 - Abstract
(1) Background: The serum ferritin cut-off to define absolute iron deficiency is not well-established. The aim of the present study was to determine a clinically relevant ferritin threshold by using early serum biomarkers of iron deficiency such as hepcidin and the soluble transferrin receptor; (2) Methods: Two hundred and twenty-eight asymptomatic subjects attending a hospital as outpatients between 1st April 2020 and 27th February 2022 were selected. Iron metabolism parameters as part of the blood analysis were requested by their doctor and included in the study. Then, they were classified into groups according to their ferritin levels and iron-related biomarkers in serum were determined, quantified, and compared between ferritin score groups and anemic subjects. (3) Results: Serum ferritin levels below 50 ng/mL establish the point from which the serum biomarker, the soluble transferrin receptor to hepcidin ratio (sTfR/Hep ratio), begins to correlate significantly with ferritin levels. (4) Conclusion: Ferritin levels ≤ 50 ng/mL are indicative of early iron deficiency; hence, this should be considered as a clinically relevant cut-off for iron deficiency.
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- 2022
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10. Immunometabolism is a key factor for the persistent spontaneous elite control of HIV-1 infectionResearch in context
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Laura Tarancon-Diez, Esther Rodríguez-Gallego, Anna Rull, Joaquim Peraire, Consuelo Viladés, Irene Portilla, María Reyes Jimenez-Leon, Verónica Alba, Pol Herrero, Manuel Leal, Ezequiel Ruiz-Mateos, and Francesc Vidal
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Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Approximately 25% of elite controllers (ECs) lose their virological control by mechanisms that are only partially known. Recently, immunovirological and proteomic factors have been associated to the loss of spontaneous control. Our aim was to perform a metabolomic approach to identify the underlying mechanistic pathways and potential biomarkers associated with this loss of control. Methods: Plasma samples from EC who spontaneously lost virological control (Transient Controllers, TC, n = 8), at two and one year before the loss of control, were compared with a control group of EC who persistently maintained virological control during the same follow-up period (Persistent Controllers, PC, n = 8). The determination of metabolites and plasma lipids was performed by GC-qTOF and LC-qTOF using targeted and untargeted approaches. Metabolite levels were associated with the polyfunctionality of HIV-specific CD8+T-cell response. Findings: Our data suggest that, before the loss of control, TCs showed a specific circulating metabolomic profile characterized by aerobic glycolytic metabolism, deregulated mitochondrial function, oxidative stress and increased immunological activation. In addition, CD8+ T-cell polyfunctionality was strongly associated with metabolite levels. Finally, valine was the main differentiating factor between TCs and PCs. Interpretation: All these metabolomic differences should be considered not only as potential biomarkers but also as therapeutic targets in HIV infection. Fund: This work was supported by grants from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Fondos FEDER; Red de Investigación en Sida, Gilead Fellowship program, Spanish Ministry of Education and Spanish Ministry of Economy and Competitiveness. Keywords: Elite controllers, Energy metabolism, HIV-1, Immunometabolism, Loss of control, Metabolomic profile
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- 2019
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11. Immune Correlates of Natural HIV Elite Control and Simultaneous HCV Clearance—Supercontrollers
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Beatriz Dominguez-Molina, Sara Ferrando-Martinez, Laura Tarancon-Diez, Jose Hernandez-Quero, Miguel Genebat, Francisco Vidal, Mª Angeles Muñoz-Fernandez, Manuel Leal, Richard Koup, and Ezequiel Ruiz-Mateos
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HIV ,controllers ,HCV ,spontaneous clearance ,T-cells ,pDCs ,Immunologic diseases. Allergy ,RC581-607 - Abstract
HIV-elite controllers are a minority group of HIV-infected patients with the ability to maintain undetectable HIV viremia for long time periods without antiretroviral treatment. A small group of HIV-controllers are also able to spontaneously clear the hepatitis C virus (HCV) whom we can refer to as “supercontrollers.” There are no studies that explore immune correlates looking for the mechanisms implicated in this extraordinary phenomenon. Herein, we have analyzed HCV- and HIV-specific T-cell responses, as well as T, dendritic and NK cell phenotypes. The higher HCV-specific CD4 T-cell polyfunctionality, together with a low activation and exhaustion T-cell phenotype was found in supercontrollers. In addition, the frequency of CD8 CD161high T-cells was related with HIV- and HCV-specific T-cells polyfunctionality. Interesting features regarding NK and plasmacytoid dendritic cells (pDCs) were found. The study of the supercontroller's immune response, subjects that spontaneously controls both chronic viral infections, could provide further insights into virus-specific responses needed to develop immunotherapeutic strategies in the setting of HIV cure or HCV vaccination.
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- 2018
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12. Long-term Persistent Elite HIV-controllers: The Right Model of Functional Cure
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Laura Tarancon-Diez, Beatriz Dominguez-Molina, Pompeyo Viciana, Luis Lopez-Cortes, and Ezequiel Ruiz-Mateos
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Medicine ,Medicine (General) ,R5-920 - Published
- 2018
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13. Caecum OX40+CD4 T-cell subset associates with mucosal damage and key markers of disease in treated HIV-infection
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Isaac Rosado-Sánchez, Inés Herrero-Fernández, Salvador Sobrino, Ana E. Carvajal, Miguel Genebat, Laura Tarancón-Díez, María Carmen Garcia-Guerrero, María Carmen Puertas, Rocío M. de Pablos, Rocío Ruiz, Javier Martinez-Picado, Manuel Leal, and Yolanda M. Pacheco
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Caecum ,HIV ,OX40 ,Thymus ,GALT ,Microbiology ,QR1-502 - Abstract
Background: Blood OX40-expressing CD4 T-cells from antiretroviral (ART)-treated people living with HIV (PWH) were found to be enriched for clonally-expanded HIV sequences, hence contributing to the HIV reservoir. OX40-OX40L is also a checkpoint regulator of inflammation in multiple diseases. We explored gut mucosal OX40+CD4+ T-cells and their potential significance in HIV disease. Methods: Biopsies of caecum and terminal-ileum of ART-treated PWH (n = 32) were obtained and mucosal damage and HIV reservoir were assessed. Mucosal OX40+ and Ki67+ CD4 T-cell subsets, as well as several tissue T-cell subsets modulating mucosal integrity and homeostasis (Th17, Th22, Treg, Tc17, Tc22, IL17+TCRγδ, IL22+TCRγδ) were quantified. Inflammatory-related markers, T-cell activation and thymic output were also determined in blood samples. Correlations were explored using Spearman rank test and corrected for multiple comparisons by Benjamini-Hochberg. Results: Compared to healthy controls, a high frequency of mucosal, mainly caecum, CD4 T-cells were OX40+ in PWH. Such frequency strongly correlated with nadir CD4 (r = −0.836; p
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- 2023
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14. Polyfunctional HIV-1 specific response by CD8+ T lymphocytes expressing high levels of CD300a
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Francisco Borrego, Miguel Genebat, Ane Orrantia, Ezequiel Ruiz-Mateos, Manuel Leal, Joana Vitallé, Leire Gamboa-Urquijo, Laura Tarancon-Diez, Iñigo Terrén, Olatz Zenarruzabeitia, [Vitallé,J, Terrén,I, Gamboa-Urquijo,L, Orrantia,A, Borrego,F, Zenarruzabeitia,O] Biocruces Bizkaia Health Research Institute, Immunopathology Group, Barakaldo, Spain. [Tarancón-Díez,L, Genebat,M, Leal,M, Ruiz-Mateos,E] Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, University of Seville, CSIC, Seville, Spain. [Tarancón-Díez,L] Laboratory of Molecular Immuno-Biology, Gregorio Marañón University Hospital, Health Research Institute, Madrid, Spain. [Leal,M] Internal Medicine Service, Santa Ángela de la Cruz Viamed Hospital, Sevilla, Spain. [Borrego,F] Ikerbasque, Basque Foundation for Science, Bilbao, Spain., This study was supported by a grant from 'Plan Estatal de I+ D+ I 2013–2016, ISCIII-Subdirección de Evaluación y Fomento de la Investigación-Fondo Europeo de Desarrollo Regional (FEDER) (Grant PI13/00889)' and Marie Curie Actions, Career Integration Grant, European Commission (Grant CIG 631674). Joana Vitallé and Iñigo Terrén are recipients of a predoctoral contract funded by the Department of Education, Basque Government (PRE_2017_2_0242 and PRE_2018_1_0032). Joana Vitallé and Iñigo Terrén are recipients of a fellowship from the Jesús de Gangoiti Barrera Foundation (FJGB15/008 and FJGB17/003). Laura Tarancón-Díez was supported by Instituto de Salud Carlos III, PFIS (FI00/00431). Olatz Zenarruzabeitia is recipient of a postdoctoral contract funded by 'Instituto de Salud Carlos III-Contratos Sara Borrell 2017 (CD17/0128)' and the European Social Fund (ESF)-The ESF invests in your future. Ezequiel Ruiz-Mateos is supported by Programa Nicolás Monardes, C0032-2017, Consejería de Salud y Bienestar Social, Junta de Andalucía. Francisco Borrego is an Ikerbasque Research Professor, Ikerbasque, Basque Foundation for Science., Instituto de Salud Carlos III, European Commission, Eusko Jaurlaritza, Fundación Jesús de Gangoiti Barrera, Junta de Andalucía, and Ikerbasque Basque Foundation for Science
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0301 basic medicine ,Receptor expression ,medicine.medical_treatment ,T-Lymphocytes ,lcsh:Medicine ,HIV Infections ,CD8-Positive T-Lymphocytes ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,0302 clinical medicine ,Cytotoxic T cell ,Receptors, Immunologic ,Receptor ,lcsh:Science ,Cells, Cultured ,Multidisciplinary ,medicine.diagnostic_test ,CD300a receptor ,Degranulation ,virus diseases ,Citocinas ,Linfocitos T ,3. Good health ,Cytokine ,medicine.anatomical_structure ,Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Antiviral Agents::Anti-Retroviral Agents::Anti-HIV Agents [Medical Subject Headings] ,030220 oncology & carcinogenesis ,Cytokines ,Diseases::Immune System Diseases::Immunologic Deficiency Syndromes::HIV Infections [Medical Subject Headings] ,Cell biology ,Anti-HIV Agents ,T cell ,Immunology ,Biology ,Article ,Flow cytometry ,03 medical and health sciences ,Antigens, CD ,medicine ,Humans ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides [Medical Subject Headings] ,Organisms::Viruses::RNA Viruses::Retroviridae::Lentivirus::Lentiviruses, Primate::HIV::HIV-1 [Medical Subject Headings] ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Up-Regulation [Medical Subject Headings] ,lcsh:R ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intercellular Signaling Peptides and Proteins::Cytokines [Medical Subject Headings] ,Péptidos ,030104 developmental biology ,Anatomy::Cells::Cells, Cultured [Medical Subject Headings] ,HIV-1 ,lcsh:Q ,Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Antigens, Differentiation::Antigens, CD [Medical Subject Headings] ,Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes::T-Lymphocyte Subsets [Medical Subject Headings] ,Peptides ,CD8 ,Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes::CD8-Positive T-Lymphocytes [Medical Subject Headings] - Abstract
CD300a receptor is found on different CD8+ T cell subsets and its expression has been associated to a more cytotoxic molecular signature. CD300a has an important role in some viral infections and its expression levels are known to be modulated by human immunodeficiency virus (HIV)−1 infection on several cell types. The main objective of this work was to investigate CD300a expression and its regulation during HIV-1 specific CD8+ T cell responses. CD300a receptor expression was analysed by multiparametric flow cytometry on CD8+ T lymphocytes from HIV negative donors, naive HIV-1+ individuals and HIV-1+ subjects under suppressive combined antiretroviral therapy (cART). HIV-1 specific CD8+ T cell response was studied by stimulating cells with HIV-1 derived peptides or with a Gag HIV-1 peptide. Our results showed that HIV-1 specific CD8+ T cells expressing higher levels of CD300a were more polyfunctional showing an increased degranulation and cytokine production. Moreover, we observed an up-regulation of CD300a expression after Gag HIV-1 peptide stimulation. Finally, our results demonstrated an inverse correlation between CD300a expression on CD8+ T lymphocytes and HIV disease progression markers. In conclusion, CD300a expression is associated to a better and more polyfunctional HIV-1 specific CD8+ T cell response., This study was supported by a grant from “Plan Estatal de I+ D+ I 2013–2016, ISCIII-Subdirección de Evaluación y Fomento de la Investigación-Fondo Europeo de Desarrollo Regional (FEDER) (Grant PI13/00889)” and Marie Curie Actions, Career Integration Grant, European Commission (Grant CIG 631674). Joana Vitallé and Iñigo Terrén are recipients of a predoctoral contract funded by the Department of Education, Basque Government (PRE_2017_2_0242 and PRE_2018_1_0032). Joana Vitallé and Iñigo Terrén are recipients of a fellowship from the Jesús de Gangoiti Barrera Foundation (FJGB15/008 and FJGB17/003). Laura Tarancón-Díez was supported by Instituto de Salud Carlos III, PFIS (FI00/00431). Olatz Zenarruzabeitia is recipient of a postdoctoral contract funded by “Instituto de Salud Carlos III-Contratos Sara Borrell 2017 (CD17/0128)” and the European Social Fund (ESF)-The ESF invests in your future. Ezequiel Ruiz-Mateos is supported by Programa Nicolás Monardes, C0032-2017, Consejería de Salud y Bienestar Social, Junta de Andalucía. Francisco Borrego is an Ikerbasque Research Professor, Ikerbasque, Basque Foundation for Science.
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- 2020
15. Permanent control of HIV-1 pathogenesis in exceptional elite controllers: a model of spontaneous cure
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Concepción Casado, Cristina Gálvez, Cecilio López-Galíndez, Maria Pernas, Laura Tarancon-Diez, Ramon Lorenzo-Redondo, Ezequiel Ruiz-Mateos, Javier Martinez-Picado, Carmen Rodríguez, and Maria Cristina O. Salgado
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Epidemiology ,business.industry ,Immunology ,Public Health, Environmental and Occupational Health ,Human immunodeficiency virus (HIV) ,medicine.disease_cause ,Microbiology ,QR1-502 ,Pathogenesis ,Infectious Diseases ,Virology ,Medicine ,Public aspects of medicine ,RA1-1270 ,business ,Control (linguistics) ,Elite controllers - Published
- 2019
16. Increased CD127+ and decreased CD57+ T cell expression levels in HIV-infected patients on NRTI-sparing regimens
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Jose L. Jimenez, Miguel C. Leal, M. A. Muñoz-Fernández, R. S. De Pablo-Bernal, Laura Tarancon-Diez, Ezequiel Ruiz-Mateos, Beatriz Dominguez-Molina, Alejandro González-Serna, and Sara Ferrando-Martinez
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Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,T-Lymphocytes ,T cell ,lcsh:Medicine ,HIV Infections ,Peripheral blood mononuclear cell ,General Biochemistry, Genetics and Molecular Biology ,Flow cytometry ,Interleukin-7 Receptor alpha Subunit ,03 medical and health sciences ,Basal (phylogenetics) ,CD57 Antigens ,immune system diseases ,Internal medicine ,medicine ,Homeostasis ,Humans ,Interleukin-7 receptor ,medicine.diagnostic_test ,integumentary system ,business.industry ,Research ,lcsh:R ,virus diseases ,HIV ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,Middle Aged ,030112 virology ,Regimen ,CD127 ,030104 developmental biology ,medicine.anatomical_structure ,NRTI-sparing ,Reverse Transcriptase Inhibitors ,Drug Therapy, Combination ,Female ,business ,Viral load ,CD57 ,CD8 - Abstract
Background NRTIs-sparing regimens exert favourable profiles on T-cell homeostasis associated parameters. Our aim was to analyze the effect of NRTIs sparing regimen (NRTI-sparing-cART) vs NRTIs-containing regimen (NRTI-cART), on T-cell homeostasis associated parameters in naive HIV-infected patients. Methods Biomarkers of cell survival (CD127) and replicative senescence (CD57), were measured by multiparametric flow cytometry for T-cell phenotyping on peripheral blood mononuclear cells (PBMCs) samples just before (baseline) and after 48 weeks of undetectable viral load in patients on NRTI-sparing-cART (N = 13) and NRTI-cART (N = 14). After 48 weeks a subgroup of patients (n = 5) on NRTI-cART switched to NRTI-sparing-cART for another additional 48 weeks. In vitro assays were performed on PBMCs from HIV-uninfected healthy donors exposed or not to HIV. To analyze the independent factors associated with type of cART bivariate and stepwise multivariate analysis were performed after adjusting for basal CD4+, CD8+ and nadir CD4+ T-cell counts. Results After 48 weeks of a NRTI-sparing-cART vs NRTI-cART patients have higher effector memory (EM) CD4+ CD127+ T-cell levels, lower EM CD4+ CD57+ T-cell levels, higher CD8+ CD127+ T-cell levels, lower CD8+ CD57+ T-cell levels and higher memory CD8+ T-cell levels. This effect was confirmed in the subgroup of patients who switched to NRTI-sparing-cART. In vitro assays confirmed that the deleterious effect of a NRTIs-containing regimen was due to NRTIs. Conclusions The implementation of NRTI-sparing regimens, with a favourable profile in CD127 and CD57 T-cell expression, could benefit cART-patients. These results could have potential implications in a decrease in the number of Non-AIDS events. Electronic supplementary material The online version of this article (10.1186/s12967-017-1367-5) contains supplementary material, which is available to authorized users.
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- 2017
17. High CD8 T cell percentage and HCV replication control are common features in HIV-1 controllers and HTLV-2-co-infected patients with a history of injection drug use
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Santiago Moreno, Ana Moreno, Carolina Gutierrez, Alejandro Vallejo, Laura Tarancon-Diez, Manuel Leal, María J Pérez-Elías, Fernando Dronda, Beatriz Dominguez-Molina, Ezequiel Ruiz-Mateos, María J. Ruiz-León, Instituto de Salud Carlos III, Red Española de Investigación en SIDA, Ministerio de Educación, Cultura y Deporte (España), and Comunidad de Madrid
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Adult ,Male ,Cancer Research ,Multivariate analysis ,Human immunodeficiency virus (HIV) ,HIV Infections ,Hepacivirus ,CD8-Positive T-Lymphocytes ,Virus Replication ,medicine.disease_cause ,Injection drug use ,Tertiary Care Centers ,03 medical and health sciences ,Immune system ,Virology ,Genotype ,medicine ,Humans ,Cytotoxic T cell ,Substance Abuse, Intravenous ,Retrospective Studies ,030304 developmental biology ,0303 health sciences ,Deltaretrovirus Infections ,biology ,Coinfection ,030306 microbiology ,Human T-lymphotropic virus 2 ,CD8 T cell percentage ,RNA ,virus diseases ,Middle Aged ,Viral Load ,HCV RNA load ,HIV-1 controllers ,Cross-Sectional Studies ,Infectious Diseases ,HTLV-2 ,Spain ,Immunology ,Disease Progression ,HIV-1 ,biology.protein ,Female ,Antibody - Abstract
HTLV-2/HIV-1-coinfected patients and HIV-infected patients with natural HIV-1 control show an immune capacity that allows some control of viral infections. These two groups of patients have showed an immune capacity that allows them to have some control over viral infections, very strong control of HIV-1 replication in the case of HIV-1 controllers. The purpose of this retrospective cross-sectional study was to compare viral and immunologic parameters between three cohorts of Caucasian adult HIV-1-infected patients, including HIV-1 controllers (29 patients), HTLV-2/HIV-1 chronic progressors (56 patients), and HIV-1 chronic progressors (101 patients), followed in two different tertiary University Hospitals in Spain. Demographic parameters, nadir CD4 T cell count, CD4 and CD8 T cell counts and percentage, anti-HCV antibodies, HCV RNA load, HCV genotype, HIV-1 RNA loads, and anti-HTLV-2 antibodies were analyzed. HIV-1 controllers and HTLV-2/HIV-1 chronic progressors were younger and with shorter time since HIV-1 diagnosis compared to HIV-1 chronic progressors. HIV-1 controllers and HTLV-2/HIV-1 chronic progressors had significantly higher CD8 T cell percentage (p = 0.002 and p = 0.016, respectively) and lower levels of HCV RNA loads (0.015 and 0.007, respectively) compared to that of HIV-1 chronic progressors. Multivariate analyses showed that gender and HTLV-2 infection were independently associated to HCV RNA load, while only HTLV-2 infection was independently associated to CD8 T cell percentage. The implication of HTLV-2 infection in the control of HIV-1 and HCV infections is worth being further analyze., This work was supported by the Instituto de Salud Carlos III Red Temática de Investigación Cooperativa en Sindrome de Inmunodeficiencia Adquirida (SIDA) (RD016/0025/0001, RD12/0017/0029, RD16/0025/0020 ISCIII-FEDER) and Programa Miguel Servet (CPII014/00025 to ERM); the Spanish Ministry of Education (FPU13/02451 to BDM); Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III FEDER (PI12/02283, PI16/00684 to ERM and FI14/00431 to LTD); Ayudas contratación de ayudantes de investigación y técnicos de laboratorio, Consejería de Educación, Juventud y Deporte de la Comunidad de Madrid (PEJ15/bio/tl-0064 to MJRL).
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- 2019
18. Improved CD4 T-cell profile and inflammatory levels in HIV-infected subjects on maraviroc-containing therapy is associated with better responsiveness to HBV vaccination
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Miguel Genebat, Ezequiel Ruiz-Mateos, Isaac Rosado-Sánchez, Yolanda M. Pacheco, María del Carmen Lozano, María del Mar del Pozo-Balado, Manuel Leal, Maria del Mar Rodríguez-Méndez, Inés Herrero-Fernández, and Laura Tarancon-Diez
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Senescence ,Hepatitis B virus ,business.industry ,virus diseases ,Inflammation ,Dendritic cell ,medicine.disease_cause ,Logistic regression ,Vaccination ,chemistry.chemical_compound ,chemistry ,Immunology ,medicine ,Distribution (pharmacology) ,medicine.symptom ,business ,Maraviroc - Abstract
IntroductionWe previously found that a maraviroc-containing combined antiretroviral therapy (MVC-cART) was associated with a better response to the Hepatitis B Virus (HBV) vaccine in HIV-infected subjects younger than 50 years old. We aimed here to extend our previous analysis including immunological parameters related to inflammation, T-cell and dendritic cell (DC) subsets phenotype and to explore the impact of MVC-cART on these parameters.MethodsWe analyzed baseline samples of vaccinated subjects under 50 years old (n=41). We characterized CD4 T-cells according to the distribution of their maturational subsets and the expression of activation, senescence and prone-to-apoptosis markers; we also quantified Treg-cells and main DC subsets. Linear regressions were performed to determine the impact of these variables on the magnitude of vaccine response. Binary logistic regressions were explored to analyze the impact of MVC-cART on immunological parameters. Correlations with the time of MVC exposure were also explored.ResultsMVC-cART remained independently associated with HBV-vaccine responsiveness even after adjusting by immunological variables. The %CD4+CD25hiFoxP3+ki67+ and %pDCs were also independently associated. Moreover, HIV-infected subjects on MVC-containing therapy prior to vaccination showed lower inflammatory levels, activated CD4 T-cells and frequency of Treg cells and higher frequency of recent thymic emigrants.ConclusionTreg-cell levels negatively impacted the HBV-vaccine response, whereas higher pDCs levels and a MVC-cART prior to vaccination were associated with better responsiveness. These factors together with the improved phenotypic CD4 T-cell profile and the lower inflammatory levels found in subjects with a MVC-cART prior HBV vaccination could contribute to their enhanced vaccine response.
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- 2018
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19. Long-term Persistent Elite HIV-controllers: The Right Model of Functional Cure
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Pompeyo Viciana, Laura Tarancon-Diez, Luis F. López-Cortés, Ezequiel Ruiz-Mateos, and Beatriz Dominguez-Molina
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0301 basic medicine ,Gerontology ,Adult ,Male ,HLA B*07 C*07 ,T-Lymphocytes ,030106 microbiology ,Human immunodeficiency virus (HIV) ,lcsh:Medicine ,HIV Infections ,HIV-1 DNA ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,HIV Long-Term Survivors ,03 medical and health sciences ,Sexual and Gender Minorities ,medicine ,Humans ,Homosexuality, Male ,Phylogeny ,lcsh:R5-920 ,Immune activation ,lcsh:R ,General Medicine ,Term (time) ,Incomplete western blot ,030104 developmental biology ,Sexual Partners ,Elite control ,Elite ,Commentary ,HIV-1 ,Partner ,lcsh:Medicine (General) ,Genetic Background ,Research Paper - Abstract
Background We describe a homosexual man who strongly controlled HIV-1 for ten years despite lack of protective genetic background. Methods HIV-1 DNA was measured in blood and other tissues. Cell susceptibility was evaluated with various strains. HIV-1-specific (CD4 and CD8 activation markers and immune check points) and NK cells responses were assessed; KIRs haplotypes and HLA alleles were determined. Findings Two HIV-1 RNA copies/mL of plasma were detected in 2009, using an ultra-sensitive assay. HIV-DNA was detected at 1.1 and 2 copies/106 PBMCs in 2009 and 2015 respectively, at 1.2 copies/106 cells in rectal cells in 2011. WBs showed weak reactivity with antibodies to gp160, p55 and p25 from 2007 to 2014, remaining incomplete in 2017. CD4 T cells were susceptible to various strains including HIVKON, a primary isolate of his own CRF02_AG variant. CD8 T cells showed a strong poly-functional response against HIV-Gag, producing mainly IFN-γ; a robust capacity of antibody-dependant cell cytotoxicity (ADCC) was observed in NK cells. Case patient was group B KIR haplotype. Neutralizing antibodies were not detected. CD4 and CD8 blood T cells showed normal proportions without increased activation markers. Phylogenetic analyses identified the same CRF02_AG variant in his partner. The patient and his partner were heterozygous for the CCR5ΔD32 deletion and shared HLA-B*07, C*07 non-protective alleles. Interpretation This thorough description of the natural history of an individual controlling HIV-1 in various compartments for ten years despite lack of protective alleles, and of his partner, may have implications for strategies to cure HIV-1 infection., Highlights • We described a MSM, elite controller despite pejorative genetic background. • The patient had two HLA pejoratives alleles and no protective alleles. • The partner was infected by the same strain. • The genetic backgrounds of the patient and partner, and the virus could interact with each other to lead to elite control. We considered all the evidence about elite control, HLA, ADCC and NK, using Medline/PubMed. We described a MSM, elite controller despite non-protective genetic background, explored extensively the patient: sequential WBs, RNA in plasma (ultrasensitive assay), DNA in PBMC/GALT, cell susceptibility, HIV-1 responses in PBMC/LNMC, neutralizing antibodies, CD3-CD56 + NK, ADCC, KIRs. He had one HLA pejorative and no protective alleles. The partner was infected by the same strain, his genetic background was studied. The genetic background of the exposed person, of the source, and the viral strain could interact with each other to lead to elite control.
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- 2018
20. Improved CD4 T cell profile in HIV-infected subjects on maraviroc-containing therapy is associated with better responsiveness to HBV vaccination
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Inés Herrero-Fernández, Isaac Rosado-Sánchez, Miguel Genebat, Laura Tarancón-Díez, María Mar Rodríguez-Méndez, María Mar Pozo-Balado, Carmen Lozano, Ezequiel Ruiz-Mateos, Manuel Leal, and Yolanda M. Pacheco
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Maraviroc (MVC) ,CD4 T-cell ,Ki67 ,Activation ,Treg ,hsCRP ,Medicine - Abstract
Abstract Background Maraviroc-containing combined antiretroviral therapy (MVC-cART) improved the response to the hepatitis B virus (HBV) vaccine in HIV-infected subjects younger than 50 years old. We aimed here to explore the effect of this antiretroviral therapy on different immunological parameters that could account for this effect. Methods We analysed baseline samples of vaccinated subjects under 50 years old (n = 41). We characterized the maturational subsets and the expression of activation, senescence and prone-to-apoptosis markers on CD4 T-cells; we also quantified T-regulatory cells (Treg) and dendritic cell (DC) subsets. We used binary logistic regression to evaluate the immunological impact of MVC-cART, correlation with MVC exposure and linear regression for association with the magnitude of the HBV vaccine response. Results HIV-infected subjects on MVC-cART prior to vaccination showed increased recent thymic emigrants levels and reduced myeloid-DC levels. A longer exposure to MVC-cART was associated with lower frequencies of Tregs and activated and proliferating CD4 T-cells. Furthermore, the frequencies of activated and proliferating CD4 T-cells were inversely associated with the magnitude of the HBV vaccine response. Conclusion The beneficial effect of MVC-cART in the HBV vaccine response in subjects below 50 years old could be partially mediated by its reducing effect on the frequencies of activated and proliferating CD4 T-cells prior to vaccination.
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- 2018
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21. Altered Expression of CD300a Inhibitory Receptor on CD4+ T Cells From Human Immunodeficiency Virus-1-Infected Patients: Association With Disease Progression Markers
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Joana Vitallé, Iñigo Terrén, Leire Gamboa-Urquijo, Ane Orrantia, Laura Tarancón-Díez, Miguel Genebat, Ezequiel Ruiz-Mateos, Manuel Leal, Susana García-Obregón, Olatz Zenarruzabeitia, and Francisco Borrego
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CD300 ,CD300a ,human immunodeficiency virus-1 ,CD4 T cells ,PD1 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The ability of the CD300a inhibitory receptor to modulate immune cell functions and its involvement in the pathogenesis of many diseases has aroused a great interest in this molecule. Within human CD4+ T lymphocytes from healthy donors, the inhibitory receptor CD300a is differentially expressed among different T helper subsets. However, there are no data about the expression and regulation of CD300a receptor on CD4+ T cells from human immunodeficiency virus (HIV)-1-infected patients. The objective of this study was to investigate the expression of CD300a on CD4+ T cells from HIV-infected patients on suppressive combined antiretroviral therapy (cART) and cART naïve patients. Our results have demonstrated that the expression levels of this inhibitory receptor were higher on CD4+ T cells from HIV-1 infected subjects compared with healthy donors, and that cART did not reverse the altered expression of CD300a receptor in these patients. We have observed an increase of CD300a expression on both PD1+CD4+ and CD38+CD4+ T cells from HIV-1 infected people. Interestingly, a triple positive (CD300a+PD1+CD38+) subset was expanded in naïve HIV-1 infected patients, while it was very rare in healthy donors and patients on cART. Finally, we found a negative correlation of CD300a expression on CD4+ T lymphocytes and some markers associated with HIV-1 disease progression. Thus, our results show that HIV-1 infection has an impact in the regulation of CD300a inhibitory receptor expression levels, and further studies will shed light into the role of this cell surface receptor in the pathogenesis of HIV infection.
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- 2018
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