Abstract
Persistent immune activation plays a central role in driving Human Immunodeficiency Virus (HIV) disease progression. Whether CD4+CD25+ regulatory T cells (Tregs) are harmful by suppressing HIV-specific immune responses and/or beneficial through a decrease in immune activation remains debatable. We analysed the relationship between proportion and number of regulatory T cells (Tregs) and immune activation in HIV-infected patients interrupting an effective antiretroviral therapy (ART). Twenty-five patients were included in a substudy of a prospective multicenter trial of treatment interruption (TI) (ANRS 116). Proportions and numbers of Tregs and the proportion of activated CD4 and CD8 T cells were assessed at baseline and month 12 (M12) of TI. Specific anti-HIV CD4 and CD8 responses were investigated at baseline and M12. Non parametric univariate analyses and multivariate linear regression models were conducted. At baseline, the proportion of Tregs negatively correlated with the proportion of HLA-DR+CD8+T cells (r = −0.519). Following TI, the proportion of Tregs increased from 6.3% to 7.2% (p = 0.029); absolute numbers of Tregs decreased. The increase in the proportion of HLA-DR+CD38+CD8+T cells was significantly related to the increase in proportion of Tregs (p = 0.031). At M12, the proportion of Tregs did not negatively correlate with CD8 T-cell activation. Nevertheless, Tregs retain a suppressive function since depletion of Treg-containing CD4+CD25+ cells led to an increase in lymphoproliferative responses in most patients studied. Our data suggest that Tregs are efficient in controlling residual immune activation in patients with ART-mediated viral suppression. However, the insufficient increase in the proportion and/or the decrease in the absolute number of Tregs result in a failure to control immune activation following TI.Trial RegistrationClinicalTrials.gov NCT00118677
Highlights
Human Immunodeficiency Virus (HIV) infection is associated with a progressive depletion of CD4+ T lymphocytes and defective HIV specific T-cell responses
Data from the present study strongly suggest that regulatory T cells are capable of controlling residual immune activation in patients under combination antiretroviral therapy (cART) but not the immune activation resulting from viral replication after cART interruption
Patients included in the present study were treated early in the course of HIV infection and exhibited, at baseline under cART, high CD4 cell counts, undetectable plasma HIV-RNA and relatively low levels of HIV-DNA in Peripheral blood mononuclear cells (PBMCs) [30]
Summary
HIV infection is associated with a progressive depletion of CD4+ T lymphocytes and defective HIV specific T-cell responses. In HIV/SIV infection, Tregs, capable of suppressing HIV/SIV-specific immune responses, are detected in peripheral blood and lymphoid tissues and may contribute to immune suppression [8,9,10,11,12,13]. Results regarding the ability of Tregs to control chronic immune activation associated with HIV/SIV infection were not consistent among studies [19,20,21,22,23]. These discrepancies may result from a disparity in the markers used to identify Tregs, the compartments studied (i.e. peripheral blood vs lymphoid tissues) and the stage of the disease. Lim et al [22] recently validated the use of CD4+CD25+CD127low/2 as a phenotypic marker of CD4 Treg cells in antiretroviral naıve HIV-infected patients
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