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      Thymic Function as a Predictor of Immune Recovery in Chronically HIV-Infected Patients Initiating Antiretroviral Therapy

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          Abstract

          Poor immunological responders (PIR) are HIV-infected patients with virologic suppression upon antiretroviral therapy (ART) but persistently low CD4 + T cell counts. Early identification of PIR is important given their higher morbimortality compared to adequate immune responders (AIR). In this study, 33 patients severely lymphopenic at ART onset, were followed for at least 36 months, and classified as PIR or AIR using cluster analysis grounded on their CD4 + T cell count trajectories. Based on a variety of immunological parameters, we built predictive models of PIR/AIR outcome using logistic regression. All PIR had CD4 + T cell counts consistently below 500 cells/μL, while all AIR reached this threshold. AIR showed a higher percentage of recent thymic emigrants among CD4 + T cells; higher numbers of sj-TRECs and greater sj/β TREC ratios; and significant increases in thymic volume from baseline to 12 months of ART. We identified mathematical models that correctly predicted PIR/AIR outcome after 36 months of therapy in 77–87% of the cases, based on observations made until 2–6 months after ART onset. This study highlights the importance of thymic activity in the immune recovery of severely lymphopenic patients, and may help to select the patients that will benefit from closer follow-up or novel therapeutic approaches.

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          Changes in thymic function with age and during the treatment of HIV infection.

          The thymus represents the major site of the production and generation of T cells expressing alphabeta-type T-cell antigen receptors. Age-related involution may affect the ability of the thymus to reconstitute T cells expressing CD4 cell-surface antigens that are lost during HIV infection; this effect has been seen after chemotherapy and bone-marrow transplantation. Adult HIV-infected patients treated with highly active antiretroviral therapy (HAART) show a progressive increase in their number of naive CD4-positive T cells. These cells could arise through expansion of existing naive T cells in the periphery or through thymic production of new naive T cells. Here we quantify thymic output by measuring the excisional DNA products of TCR-gene rearrangement. We find that, although thymic function declines with age, substantial output is maintained into late adulthood. HIV infection leads to a decrease in thymic function that can be measured in the peripheral blood and lymphoid tissues. In adults treated with HAART, there is a rapid and sustained increase in thymic output in most subjects. These results indicate that the adult thymus can contribute to immune reconstitution following HAART.
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            The Effect of Age on Thymic Function

            Age-related regression of the thymus is associated with a decline in naïve T cell output. This is thought to contribute to the reduction in T cell diversity seen in older individuals and linked with increased susceptibility to infection, autoimmune disease, and cancer. Thymic involution is one of the most dramatic and ubiquitous changes seen in the aging immune system, but the mechanisms which underlying this process are poorly understood. However, a picture is emerging, implicating the involvement of both extrinsic and intrinsic factors. In this review we assess the role of the thymic microenvironment as a potential target that regulates thymic involution, question whether thymocyte development in the aged thymus is functionally impaired, and explore the kinetics of thymic involution.
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              Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease.

              Highly active antiretroviral therapy (HAART) increases CD4(+) cell numbers, but its ability to correct the human immunodeficiency virus (HIV)-induced immune deficiency remains unknown. A three-phase T cell reconstitution was demonstrated after HAART, with: (i) an early rise of memory CD4(+) cells, (ii) a reduction in T cell activation correlated to the decreasing retroviral activity together with an improved CD4(+) T cell reactivity to recall antigens, and (iii) a late rise of "naïve" CD4(+) lymphocytes while CD8(+) T cells declined, however, without complete normalization of these parameters. Thus, decreasing the HIV load can reverse HIV-driven activation and CD4(+) T cell defects in advanced HIV-infected patients.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                05 February 2019
                2019
                : 10
                : 25
                Affiliations
                [1] 1Population Health Research Domain, Life and Health Sciences Research Institute, School of Medicine, University of Minho , Braga, Portugal
                [2] 2ICVS/3B's, PT Government Associate Laboratory , Braga/Guimarães, Portugal
                [3] 3Department of Onco-Hematology, Portuguese Institute of Oncology of Porto , Porto, Portugal
                [4] 4Department of Mathematics and Applications, School of Sciences, University of Minho , Braga, Portugal
                [5] 5Center of Mathematics, University of Minho , Braga, Portugal
                [6] 6INSERM, U1016, Institut Cochin , Paris, France
                [7] 7CNRS, UMR8104 , Paris, France
                [8] 8Department of Infection, Immunity and Inflammation, Université Paris Decartes , Paris, France
                [9] 9Department of Pathology & Cell Biology, Columbia University , New York, NY, United States
                [10] 10Department of Infectious Diseases, Centro Hospitalar do Porto , Porto, Portugal
                [11] 11Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet , Stockholm, Sweden
                Author notes

                Edited by: Francesca Chiodi, Karolinska Institute (KI), Sweden

                Reviewed by: Antonio Bandeira, Center for the National Scientific Research (CNRS), France; Ruy Ribeiro, Los Alamos National Laboratory (DOE), United States

                *Correspondence: Margarida Correia-Neves mcorreianeves@ 123456med.uminho.pt

                This article was submitted to Viral Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2019.00025
                6370619
                30804925
                0a33dc1a-999a-4ea7-81a5-a738362598ef
                Copyright © 2019 Rb-Silva, Nobrega, Azevedo, Athayde, Canto-Gomes, Ferreira, Cheynier, Yates, Horta and Correia-Neves.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 08 October 2018
                : 07 January 2019
                Page count
                Figures: 5, Tables: 3, Equations: 4, References: 61, Pages: 13, Words: 9508
                Funding
                Funded by: European Regional Development Fund 10.13039/501100008530
                Funded by: Fundação para a Ciência e a Tecnologia 10.13039/501100001871
                Funded by: Gilead Sciences 10.13039/100005564
                Categories
                Immunology
                Original Research

                Immunology
                poor immunological responders,predictive modeling,immune recovery,cd4+ t cells,thymic function,immune activation,antiretroviral therapy,hiv infection

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