Analysis of Suppressor and Non-Suppressor FOXP3+ T Cells in HIV-1-Infected Patients

Abstract

Recently, it was shown that peripheral blood FOXP3+CD4+ T cells are composed of three phenotypic and functionally distinct subpopulations. Two of them having in vitro suppressive effects were characterized as resting Treg cells (rTregs) and activated Treg cells (aTregs). A third subset, identified as FOXP3+ non-Tregs, does not display any suppressor activity and produce high levels of Th1 and Th17 cytokines upon stimulation. In the present study we focus on the characteristics of these three subsets of FOXP3+CD4+ T cells in untreated HIV-1-infected patients. We found that the absolute counts of rTregs, aTregs and FOXP3+ non-Tregs were reduced in HIV-1 patients compared with healthy donors. The relative frequency of rTregs and aTregs was similar in HIV-1 patients and healthy donors, while the frequency of FOXP3+ non-Tregs was significantly higher in HIV-1 patients, reaching a maximum in those patients with the lower values of CD4 counts. Contrasting with the observations made in FOXP3- CD4+ T cells, we did not find a negative correlation between the number of rTregs, aTregs or FOXP3+ non-Tregs and virus load. Studies performed with either whole PBMCs or sorted aTregs and FOXP3+ non-Tregs cells showed that these two populations of FOXP3+ T cells were highly permissive to HIV-1 infection. Upon infection, FOXP3+ non-Tregs markedly down-regulates its capacity to produce Th1 and Th17 cytokines, however, they retain the ability to produce substantial amounts of Th2 cytokines. This suggests that FOXP3+ non-Tregs might contribute to the polarization of CD4+ T cells into a Th2 profile, predictive of a poor outcome of HIV-1-infected patients.

CD4+FOXP3+ Regulatory T-Cell Subsets in Human Immunodeficiency Virus Infection

“…Regarding the association of naïve Treg cell numbers and parameters of disease in HIV infection, naïve Treg cell numbers positively correlate with CD4 count in both healthy donors and HIV-infected patients (26, 31, 76) independently from the stage of the disease. No association (76) or only weak inverse correlation (26, 31) between levels of HIV RNA levels and number of naïve Tregs have been reported.…”

“…CD45RA+ FOXP3low CD25low Treg counts have been reported to be significantly reduced in HIV-infected patients when compared with healthy donors (26, 76). When different HIV diseases stages are taken into account naïve Treg counts reduction seems to be exclusively restricted to the PHI phase, while no difference is observed when viremic and aviremic chronically infected patients are considered (26).…”

“…Proportions of CD31+ among naïve Treg are not affected during acute or chronic HIV infection indicating preserved Treg thymic differentiation (77). Naïve Treg express high levels of the HIV co-receptor CXCR4 while CCR5 is barely detectable at their surface (76–78). In vitro experiments have demonstrated that CD45RA+ naïve Treg are more susceptible to HIV infection when compared to conventional CD45RA+ naïve CD4 T cells (76, 78).…”

“…Naïve Treg express high levels of the HIV co-receptor CXCR4 while CCR5 is barely detectable at their surface (76–78). In vitro experiments have demonstrated that CD45RA+ naïve Treg are more susceptible to HIV infection when compared to conventional CD45RA+ naïve CD4 T cells (76, 78). Accordingly to their phenotype naïve Treg were more susceptible to in vitro infection when CXCR4-tropic strain (HIV-1 IIIB) was used rather than CCR5-tropic strain using HIV-1 BaL (76).…”

“…No association (76) or only weak inverse correlation (26, 31) between levels of HIV RNA levels and number of naïve Tregs have been reported. Finally, naïve Treg cell numbers correlate neither with global CD8 T-cell activation nor with HIV-specific CD8 T-cell responses (26).…”