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      Increased Regulatory T-Cell Percentage Contributes to Poor CD4 + Lymphocytes Recovery: A 2-Year Prospective Study After Introduction of Antiretroviral Therapy

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          Abstract

          Background.  The primary aim of this study was to determine the impact of regulatory T cells (Tregs) percentage on immune recovery in human immunodeficiency virus (HIV)-infected patients after antiretroviral therapy introduction.

          Methods.  A 2-year prospective study was conducted in HIV-1 chronically infected naive patients with CD4 count <500 cells/mm 3. Regulatory T cells were identified as CD4 +CD25 highCD127 low cells among CD4 + lymphocytes. Effect of Treg percentage at inclusion on CD4 evolution overtime was analyzed using a mixed-effect Poisson regression for count data.

          Results.  Fifty-eight patients were included (median CD4 = 293/mm 3, median Treg percentage = 6.1%). Percentage of Treg at baseline and CD4 nadir were independently related to the evolution of CD4 absolute value according to time: (1) at any given nadir CD4 count, 1% increase of initial Treg was associated with a 1.9% lower CD4 absolute value at month 24; (2) at any given Treg percentage at baseline, 10 cell/mm 3 increase of CD4 nadir was associated with a 2.4% increase of CD4 at month 24; and (3) both effects did not attenuate with time. The effect of Treg at baseline on CD4 evolution was as low as the CD4 nadir was high.

          Conclusions.  Regulatory T-cell percentage at baseline is a strong independent prognostic factor of immune recovery, particularly among patients with low CD4 nadir.

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          Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment.

          Colleen Kelley, Christina Kitchen, Peter W. Hunt … (2009)
          Although antiretroviral therapy has the ability to fully restore a normal CD4(+) cell count (>500 cells/mm(3)) in most patients, it is not yet clear whether all patients can achieve normalization of their CD4(+) cell count, in part because no study has followed up patients for >7 years. Three hundred sixty-six patients from 5 clinical cohorts who maintained a plasma human immunodeficiency virus (HIV) RNA level 1000 copies/mL for at least 4 years after initiation of antiretroviral therapy were included. Changes in CD4(+) cell count were evaluated using mixed-effects modeling, spline-smoothing regression, and Kaplan-Meier techniques. The majority (83%) of the patients were men. The median CD4(+) cell count at the time of therapy initiation was 201 cells/mm(3) (interquartile range, 72-344 cells/mm(3)), and the median age was 47 years. The median follow-up period was 7.5 years (interquartile range, 5.5-9.7 years). CD4(+) cell counts continued to increase throughout the follow-up period, albeit slowly after year 4. Although almost all patients (95%) who started therapy with a CD4(+) cell count 300 cells/mm(3) were able to attain a CD4(+) cell count 500 cells/mm(3), 44% of patients who started therapy with a CD4(+) cell count 500 cells/mm(3) over a mean duration of follow-up of 7.5 years; many did not reach this threshold by year 10. Twenty-four percent of individuals with a CD4(+) cell count <500 cells/mm(3) at year 4 had evidence of a CD4(+) cell count plateau after year 4. The frequency of detectable viremia ("blips") after year 4 was not associated with the magnitude of the CD4(+) cell count change. A substantial proportion of patients who delay therapy until their CD4(+) cell count decreases to <200 cells/mm(3) do not achieve a normal CD4(+) cell count, even after a decade of otherwise effective antiretroviral therapy. Although the majority of patients have evidence of slow increases in their CD4(+) cell count over time, many do not. These individuals may have an elevated risk of non-AIDS-related morbidity and mortality.
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            CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression.

            Robert Moore, Jeanne Keruly (2007)
            Sustained suppression of the human immunodeficiency virus (HIV) type 1 RNA load with the use of highly active antiretroviral therapy (HAART) results in immunologic improvement, but it is not clear whether the CD4(+) cell count increases to normal levels or whether it reaches a less-than-normal plateau. We characterized the increase in the CD4(+) cell count in patients in clinical practice who maintained sustained viral suppression for up to 6 years. All patients were from the Johns Hopkins HIV Clinical Cohort, a longitudinal observational study of patients receiving primary HIV care in Baltimore, Maryland, who were observed for >1 year while receiving HAART and who had sustained suppression of the HIV RNA load at 350 cells/microL, and we assessed the development of clinical events (death and new acquired immunodeficiency syndrome-defining illness) by Kaplan-Meier analysis. A total of 655 patients were observed for a median of 46 months (range, 13-72 months). The median change from baseline to most recent CD4(+) cell count was +274 cells/microL, with 92% of patients having an increase in CD4(+) cell count. By 6 years, the median CD4(+) cell count was 493 cells/microL among patients with baseline CD4(+) cell counts 350 cells/microL. In addition to baseline CD4(+) cell count, injection drug use and older age were associated with a lesser CD4(+) cell count response, and duration of therapy was associated with a greater CD4(+) cell count response. Only patients with baseline CD4(+) cell counts >350 cells/microL returned to nearly normal CD4(+) cell counts after 6 years of follow-up. Significant increases were observed in all CD4(+) cell count strata during the first year, but there was a lower plateau CD4(+) cell count at lower baseline CD4(+) cell strata. These data suggest that waiting to start HAART at lower CD4(+) cell counts will result in the CD4(+) cell count not returning to normal levels.
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              Coordination of early protective immunity to viral infection by regulatory T cells.

              Nhan T. Pham, Lianne Hsing, Alexander Rudensky … (2008)
              Suppression of immune responses by regulatory T cells (Tregs) is thought to limit late stages of pathogen-specific immunity as a means of minimizing associated tissue damage. We examined a role for Tregs during mucosal herpes simplex virus infection in mice, and observed an accelerated fatal infection with increased viral loads in the mucosa and central nervous system after ablation of Tregs. Although augmented interferon production was detected in the draining lymph nodes (dLNs) in Treg-deprived mice, it was profoundly reduced at the infection site. This was associated with a delay in the arrival of natural killer cells, dendritic cells, and T cells to the site of infection and a sharp increase in proinflammatory chemokine levels in the dLNs. Our results suggest that Tregs facilitate early protective responses to local viral infection by allowing a timely entry of immune cells into infected tissue.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Open Forum Infect Dis
                Journal ID (iso-abbrev): Open Forum Infect Dis
                Journal ID (publisher-id): ofid
                Journal ID (hwp): ofids
                Title: Open Forum Infectious Diseases
                Publisher: Oxford University Press
                ISSN (Electronic): 2328-8957
                Publication date Collection: April 2015
                Publication date (Electronic): 01 May 2015
                Volume: 2
                Issue: 2
                Electronic Location Identifier: ofv063
                Affiliations
                [1 ]Immunology Laboratory, Hospices Civils de Lyon, Hôpital Edouard Herriot , France
                [2 ]Infectious and Tropical Disease Unit
                [3 ]Lyon-1 University
                [4 ]Centre International de Recherche en Infectiologie, Centre CNRS U1111 (INSERM ) - UMR5308, ENS de Lyon, UCBL1
                [5 ]Service de Biostatistique, Hospices Civils de Lyon
                [6 ]Equipe Biostatistique Santé CNRS UMR 5558 , Villeurbanne
                [7 ]Virology Laboratory, Hospices Civils de Lyon, Hôpital Croix-Rousse , France
                Author notes
                Correspondence: Tristan Ferry, MD, PhD, Infectious and Tropical Disease Unit, Hospices Civils de Lyon, Hopital de La Croix-Rousse, 103 Grande Rue de la Croix Rousse, 69317 cedex 04, Lyon, France ( tristan.ferry@ 123456chu-lyon.fr ).
                Article
                Publisher ID: ofv063
                DOI: 10.1093/ofid/ofv063
                PMC ID: 4473110
                PubMed ID: 26110165
                SO-VID: d9520863-51e6-41ff-ad35-e7ab495a6ca5
                Copyright © © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com.

                History
                Date received : 16 February 2015
                Date accepted : 27 April 2015
                Page count
                Pages: 6
                Categories
                Subject: Major Articles
                Custom metadata
                cover-date Spring 2015

                Keywords: art,immune response,immunological failure,nadir cd4,t-regulatory cells
                Data availability:
                Keywords: art, immune response, immunological failure, nadir cd4, t-regulatory cells

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