Objective:

Interleukin-7 (IL-7) responses are impaired in CD4+ T cells from HIV-infected patients, which may play a significant role in the loss of CD4+ T-cell homeostasis. We set to investigate the nature of IL-7-dependent signaling defects in patients with progressive HIV-1 infection.

Design and methods:

IL-7 signaling was compared in CD4+ T cells from viremic patients with a viral load more than 10 000 copies of HIV RNA/ml (n= 23) and from healthy blood donors (n= 23). Phosphorylation of the transcription factor STAT5 on the regulatory serine S726 and the key tyrosine Y694 was monitored by intracellular flow cytometry. Phospho-STAT5 relocalization to the nucleus was analyzed by quantitative immunofluorescence imaging.

Results:

In control CD4+ T cells, S726 phosphorylation was mostly constitutive and inducible by IL-7 to a limited extent (1.3 x, P< 0.05). In contrast, phosphorylation at Y694 was highly inducible by IL-7 (12.6 x, P< 0.0001). Progressive HIV infection led to hyperphosphorylation of both S726 and Y694 in naive CD4+ T cells, with these changes correlating together (R= 0.66, P= 0.01). Quantitative image analysis revealed an impairment in the nuclear relocalization of both forms of phospho-STAT5 in patient cells (P< 0.005 for S726; P< 0.05 for Y694). The nuclear relocalization defect correlated with increased HLA-DR expression (R= 0.75, P< 0.01), suggesting a role for chronic immune activation in perturbed IL-7 signal transduction.

Conclusion:

HIV infection perturbs IL-7 signaling by impairing the access of STAT5 to the nuclear compartment. This defect may contribute to the loss of CD4+ T-cell populations in patients with chronically high immune activation.