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Defective interleukin-2-dependent STAT5 signalling in CD8 T lymphocytes from HIV-positive patients: restoration by antiretroviral therapy

Kryworuchko, Markoa,f; Pasquier, Virginiea; Keller, Hélènea; David, Denisa; Goujard, Cécileb; Gilquin, Jacquesc; Viard, Jean-Pauld; Joussemet, Marcele; Delfraissy, Jean-Francoisb; Thèze, Jacquesa

Basic Science: Concise Communications

Background: CD8 T lymphocytes are critical in the control of HIV replication and disease progression. Our previous studies demonstrated that CD8 T cells from chronically infected patients with high virus load proliferated poorly in response to interleukin-2 (IL-2), a cytokine critical in CD8 T cell growth and differentiation, even though relatively high levels of IL-2 receptor (IL-2R) were expressed. This suggested that signal transduction defects in response to IL-2 might be involved. The STAT5 transcription factor is important in IL-2-dependent biological responses and it is known that there are defects in unstimulated CD3 and CD4 cells in HIV-infected patients.

Objective: To investigate whether the induction of STAT5 by IL-2 is altered in the CD8 T cells from HIV-positive individuals and the impact of highly active antiretroviral therapy (HAART) on its status.

Methods: CD8 T lymphocytes were purified from the peripheral blood mononuclear cells of HIV-positive patients before and after HAART. Ex vivo IL-2-induced STAT5 activation was evaluated by immunoblotting and electrophoretic mobility shift assays.

Results: CD8 T cells from a subset of untreated HIV-positive patients were unable to activate STAT5a and STAT5b proteins functionally in response to IL-2. This defect was not a result of alterations in IL-2R expression but correlated with an impaired activation of the upstream kinase Jak-3, known to mediate STAT5 activation. Overall, HAART restored Jak/STAT signalling in such patients.

Conclusions: These results further uncover a potential mechanism by which CD8 T cell function is impaired in HIV-infected patients.

From the aUnit of Cellular Immunogenetics, Institut Pasteur, Paris, the bInternal Medicine Service, Bicêtre Hospital, Le Kremlin Bicêtre, the cDepartment of Infectious Diseases, St Joseph Hospital, Paris, dClinical Immunology Service, Necker Hospital, Paris, eBlood Transfusion Centre, Percy Hospital, Clamart, France and the fDivision of Virology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

Requests for reprints to: J. Thèze, Unité d'Immunogénétique Cellulaire, Département de Médecine Moléculaire, Institut Pasteur, 25 rue du Dr Roux, 75724, Paris Cedex 15, France.

Received: 16 January 2003; revised: 4 June 2003; accepted: 7 July 2003.

© 2004 Lippincott Williams & Wilkins, Inc.