Abstract
CD4+ regulatory T cells (Tregs) are essential for the maintenance of the immune system's equilibrium, by dampening the activation of potential auto-reactive T cells and avoiding excessive immune activation. To correctly perform their function, Tregs must be maintained at the right proportion with respect to effector T cells. Since this equilibrium is frequently disrupted in individuals infected with the human immunodeficiency virus (HIV), we hypothesize that its deregulation could hamper immune reconstitution in patients with poor CD4+ T cell recovery under highly active antiretroviral therapy (HAART). We analysed Tregs percentages amongst CD4+ T cells in 53 HIV-infected patients under HAART, with suppression of viral replication and distinct levels of immune reconstitution. As controls, 51 healthy individuals were also analysed. We observed that amongst the patients with Nadir values (the lowest CD4+ T cell counts achieved) <200 cells/µL, the individuals with high Tregs percentages (≥10% of total CD4+ T cells) had the worse CD4+ T cell reconstitution. In accordance, the well-described direct correlation between the Nadir value and CD4+ T cell reconstitution is clearly more evident in individuals with high Tregs proportions. Furthermore, we observed a strong negative correlation between Tregs percentages and CD4+ T cell recovery among immunological non-responder HIV+ individuals. All together, this work shows that high Tregs frequency is an important factor associated with sub-optimal CD4+ T cell recovery. This is particularly relevant for immunological non-responders with low Nadir values. Our results suggest that the Tregs proportion might be of clinical relevance to define cut-offs for HAART initiation.
Highlights
Infection with human immunodeficiency virus (HIV) initiates a series of events that lead to profound immunosuppression, caused by functional abnormalities in the immune system, mainly due to severe depletion of CD4+ T cells [1].The introduction of highly active antiretroviral therapy (HAART) has led to very important declines in both mortality and morbidity due to HIV infection [2]; even though many patients steadily recover their CD4+ T cell compartment over several years post-HAART initiation, the degree of immune recovery achieved is highly variable
Several factors have been suggested to contribute to this limited ability of the CD4+ T cell compartment to normalise such as advanced age [8], low baseline CD4+ T cell counts [6,8,9], residual HIV replication [10], chronic immune activation [11], abrogated thymic function [12,13], gender [14,15] and genetic polymorphisms associated with increased programmed cell death [16,17]
Human Tregs were first identified on the basis of their highlevel expression of CD25 [40,41,42] and subsequently by the expression of the Forkhead-box transcription factor FOXP3 [43,44]
Summary
Infection with HIV initiates a series of events that lead to profound immunosuppression, caused by functional abnormalities in the immune system, mainly due to severe depletion of CD4+ T cells [1].The introduction of HAART has led to very important declines in both mortality and morbidity due to HIV infection [2]; even though many patients steadily recover their CD4+ T cell compartment over several years post-HAART initiation, the degree of immune recovery achieved is highly variable. The observation that the proportion of Tregs in HAART-treated aviremic HIV+ individuals is quite diverse prompted us to explore whether distinct values were associated with differences in CD4+ T cell recovery.
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