Background: It remains debatable whether CD4⁺ regulatory T cells (Treg) have a beneficial or detrimental role in HIV disease progression. Treg may either increase in number, inhibiting effector immune responses, or decrease, allowing the generalized immune activation that characterizes HIV infection to proceed uncontrolled. It is important to clarify the role of Treg, since they are a potential immunotherapeutic target.

Methods: Peripheral blood mononuclear cells (PBMC) were isolated from treatment-naïve HIV-infected (n = 39) and uninfected (n = 14) adults. Subjects with confirmed HIV seroconversion in the previous 6 months (n = 8) were defined as acutely HIV-infected. PBMC were stained extracellularly with anti-CD4-FITC, anti-CD25-PE, and anti-CD3-PerCP; and intracellularly with anti-FoxP3-APC. Treg were defined as CD4⁺CD25^hiFoxP3⁺. Immune activation was assessed by co-expression of CD38 and HLA-DR on CD4⁺ or CD8⁺ cells (anti-CD4-FITC or anti-CD8-FITC; anti-CD3-PerCP; anti-CD38-PE; anti-HLA-DR-APC). T reg were expressed as both proportion of CD4 cells and absolute Treg count.

Results:  Chronically HIV-infected adults had a greater proportion of Treg than HIV-uninfected adults (median 4.0% [IQR 2.5 to 6.5] vs 3.0% [IQR 1.7 to 4.0] total CD4⁺ cells; p = 0.03; Mann-Whitney). In contrast, acute HIV-infected and -uninfected adults had similar Treg proportions (median 3.3% [IQR 3.0 to 5.0] vs 3.0% [IQR 1.7 to 4.0] total CD4⁺ cells; p = 0.11; Mann-Whitney). There was a strong negative correlation between absolute CD4 count and proportion of Treg (R = –0.63, p = 0.0001; Spearman correlation). However, the absolute Treg count declined as CD4 count fell (R = –0.33, p = 0.07; Spearman correlation). With decline in absolute Treg count, immune activation increased in both the CD4⁺ (R = –0.41, p = 0.02; Spearman correlation) and CD8⁺ compartments (R = –0.62, p = 0.003; Spearman correlation).

Conclusions: As HIV disease progresses, Treg form a greater proportion of the total CD4⁺ pool. However, with CD4 decline, absolute Treg decline also, allowing immune activation to proceed unchecked. The relative enrichment for Treg during disease progression suggests that this subset may not be destroyed as rapidly as other CD4 cells. However, the absolute decline in Treg may perturb the homeostatic regulation of the peripheral immune system and contribute to disease progression.