Background:  Interleukin (IL) -7 and IL-2 are the major cytokines that control CD4⁺ T cell homeostasis. Both cytokines activate the JAK/STAT5 pathway and induce the expression of the survival factor Bcl-2. Since HIV is known to perturb CD4⁺ T cell homeostasis, we investigated the effect of HIV infection on cytokine-dependent signal transduction.

Methods:  Peripheral blood mononuclear cells (PBMC) from healthy blood donors (n = 8) and HIV-infected patients with viral loads >10,000 copies/mL (n = 8) were tested for responses to IL-7 and IL-2 by polychromatic flow cytometry. The phosphorylation of STAT5 and the induction of Bcl-2 were measured in different CD4⁺ T cell subpopulations:  naive (CD45RA⁺Foxp3^–), memory (CD45RA^–Foxp3^–), naive T regulatory cells (Treg) (CD45RA⁺Foxp3⁺CD25⁺), and memory Treg (CD45RA^–Foxp3⁺CD25⁺). The expression of the IL-7 receptor (CD127, gamma-c), of the IL-2 receptor (CD25, CD122, gamma-c), and of the activation marker HLA-DR were assessed on the same subpopulations.

Results:  Viremic patients showed increased HLA-DR expression in all CD4⁺ T cell compartments, consistent with generalized immune activation. Interestingly, basal levels of pSTAT5 were increased in naive and memory populations (p <0.05), suggesting a chronic activation of the JAK/STAT5 pathway in HIV infection. CD25 expression was decreased in memory Treg of viremic patients, but these cells phosphorylated STAT5 as efficiently as memory Treg from healthy donors in response to IL-2. Similarly, CD127 expression was decreased in the Mem population of viremic patients, while these cells phosphorylated STAT5 to higher levels in response to IL-7 stimulation. pSTAT5 induction correlated with CD127 expression in healthy donor CD4⁺ T cells. This correlation was maintained in patient CD4⁺ T cells, but with a steeper slope, indicative of an increased efficiency of downstream signaling events (slope = 8.53 vs 5.04; p = 0.01). In contrast to the pSTAT5 response, the induction of Bcl-2 by IL-7 was impaired in viremic patients as compared to healthy donors.

Conclusions:  These data provide evidence for an abnormal activation of the JAK/STAT5 pathway in CD4⁺ T cells of viremic patients, which may contribute to the deleterious chronic immune activation characteristic of HIV infection. In contrast, Bcl-2 induction by IL-7 was defective in viremic patients, which likely compromises the survival capacity of CD4⁺ T cells. Thus, HIV perturbs cytokine responses at multiple levels, by simultaneously inducing activation pathways and blocking survival pathways.