FOXP3 expression is upregulated in CD4T cells in progressive HIV-1 infection and is a marker of disease severity

Background: Understanding the role of different classes of T cells during HIV infection is critical to determining which responses correlate with protective immunity. To date, it is unclear whether alterations in regulatory T cell (Treg) function are contributory to progression of HIV infection. Methodology: FOXP3 expression was measured by both qRT-PCR and by flow cytometry in HIV-infected individuals and uninfected controls together with expression of CD25, GITR and CTLA-4. Cultured peripheral blood mononuclear cells were stimulated with anti-CD3 and cell proliferation was assessed by CFSE dilution. Principal Findings: HIV infected individuals had significantly higher frequencies of CD4 + FOXP3 + T cells (median of 8.11%; range 1.33%–26.27%) than healthy controls (median 3.72%; range 1.3–7.5%; P=0.002), despite having lower absolute counts of CD4 + FOXP3 + T cells. There was a significant positive correlation between the frequency of CD4 + FOXP3 + T cells and viral load (rho=0.593 P=0.003) and a significant negative correlation with CD4 count (rho= 20.423 P=0.044). 48% of our patients had CD4 counts below 200 cells/ml and these patients showed a marked elevation of FOXP3 percentage (median 10% range 4.07%–26.27%). Assessing the mechanism of increased FOXP3 frequency, we found that the high FOXP3 levels noted in HIV infected individuals dropped rapidly in unstimulated culture conditions but could be restimulated by T cell receptor stimulation. This suggests that the high FOXP3 expression in HIV infected patients is likely due to FOXP3 upregulation by individual CD4 + T cells following antigenic or other stimulation. Conclusions/Significance: FOXP3 expression in the CD4 + T cell population is a marker of severity of HIV infection and a potential prognostic marker of disease progression.