Longitudinal evaluation of regulatory T-cell dynamics on HIV-infected individuals during the first 2 years of therapy.

OBJECTIVES: A sizeable percentage of individuals infected by HIV and on antiretroviral therapy (ART) fail to increase their CD4 T-cells to satisfactory levels. The percentage of regulatory T-cells (Tregs) has been suggested to contribute to this impairment. This study aimed to address this question and to expand the analysis of Tregs subpopulations during ART. DESIGN: Longitudinal follow-up of 81 HIV-infected individuals during the first 24 months on ART. METHODS: CD4 T-cell counts, Tregs percentages, and specific Tregs subpopulations were evaluated at ART onset, 2, 6, 9, 12, 16, 20, and 24 months of ART (five individuals had no Tregs information at baseline). RESULTS: The slope of CD4 T-cell recovery was similar for individuals with moderate and with severe lymphopenia at ART onset. No evidence was found for a contribution of the baseline Tregs percentages on the CD4 T-cell counts recovery throughout ART. In comparison to uninfected individuals, Tregs percentages were higher at ART onset only for patients with less than 200 cells/µl at baseline and decreased afterwards reaching normal values. Within Tregs, the percentage of naive cells remained low in these patients. Reduced thymic export and increased proliferation of Tregs vs. conventional CD4 T cells might explain these persistent alterations. CONCLUSION: No effect of Tregs percentages at baseline was detected on CD4 T-cell recovery. However, profound alterations on Tregs subpopulations were consistently observed throughout ART for patients with severe lymphopenia at ART onset.

Poor immune reconstitution in HIV-infected patients associates with high percentage of regulatory CD4+ T cells.

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.