HIV infection perturbs interleukin-7 signaling at the step... : AIDS (original) (raw)

BASIC SCIENCE

HIV infection perturbs interleukin-7 signaling at the step of STAT5 nuclear relocalization

Landires, Ivana; Bugault, Florencea; Lambotte, Olivierb,c; de Truchis, Pierred; Slama, Laurencee; Danckaert, Annef; Delfraissy, Jean-Françoisb,c; Thèze, Jacquesa; Chakrabarti, Lisa A.a

aPasteur Institute, Cellular Immunogenetics Unit, Paris

bAssistance Publique-Hôpitaux de Paris (AP-HP), Department of Internal Medicine and Infectious Diseases, Bicêtre Hospital, Le Kremlin-Bicêtre

cInstitut National de la Santé et de la Recherche Médicale (INSERM) U1002, Le Kremlin-Bicêtre

dAP-HP, Department of Infectious and Tropical Diseases, Raymond Poincaré Hospital, Garches

eAP-HP, Department of Infectious and Tropical Diseases, Tenon Hospital. Paris

fPasteur Institute, Dynamic Imaging Platform-Imagopole, Paris, France.

Correspondence to Dr Lisa A. Chakrabarti, Institut Pasteur, Unité d’Immunogénétique Cellulaire, 25 rue du Dr Roux, 75724 Paris Cedex 15, France. Tel: +33 1 44 38 91 31; fax: +33 1 45 68 88 38; e-mail: [email protected]

Received 1 April, 2011

Revised 8 June, 2011

Accepted 23 June, 2011

Abstract

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 (1.3x, P < 0.05). In contrast, phosphorylation at Y694 was highly inducible by IL-7 (12.6x, 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.