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Interleukin-7 signalling defects in naive CD4+ T cells of HIV patients with CD4+ T-cell deficiency on antiretroviral therapy are associated with T-cell activation and senescence

Tanaskovic, Saraa; Fernandez, Soniaa; Price, Patriciaa; French, Martyn A.a,b

doi: 10.1097/QAD.0000000000000213
Basic Science

Objective: To examine the relationship of defects in interleukin (IL)-7-induced naive CD4+ T-cell homeostasis with residual immune activation and CD4+ T-cell senescence in HIV patients receiving antiretroviral therapy (ART) who exhibit persistent CD4+ T-cell deficiency.

Design: IL-7 induced proliferation of, and IL-7 receptor signalling in, total and naive CD4+ T cells of HIV patients who had low (<350 cells/μl) or normal (>500 cells/μl) CD4+ T-cell counts on ART was examined and related to markers of CD4+ T-cell activation and senescence and innate immune activation.

Methods: Total, naive (CD45RA+ CD27+) and CD31+ naive CD4+ T cells from aviremic HIV patients (n = 39) with nadir CD4+ T-cell counts less than 100 cells/μl, who had received ART for a median time of 7 (range 1–11) years, were assessed for CD127 expression, proliferation (Ki67), signal transducer and activator of transcription 5 phosphorylation (pSTAT5) and CD127 modulation following IL-7 stimulation. Changes were related to proportions of CD4+ T cells expressing HLA-DR or CD57 and plasma levels of sCD14, CXCL9 and CXCL10.

Results: Patients with CD4+ T-cell deficiency exhibited lower expression of CD127 on total, naive and CD31+ naive CD4+ T cells. Downregulation of CD127 after culture with IL-7 correlated inversely with CD4+ T-cell counts and directly with Ki67 expression. Induction of pSTAT5 in CD4+ T-cell subsets was greater in patients with normal CD4+ T-cell counts. CD127 expression correlated inversely with proportions of CD4+CD57+ T cells, and pSTAT5 induction correlated inversely with CD4+ T-cell expression of HLA-DR and CD57.

Conclusion: Defects of IL-7 signalling in HIV patients with persistent CD4+ T-cell deficiency receiving ART are associated with CD4+ T-cell activation and senescence.

aSchool of Pathology and Laboratory Medicine, University of Western Australia

bDepartment of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine, Perth, Western Australia, Australia.

Correspondence to Martyn French, School of Pathology and Laboratory Medicine, University of Western Australia, Level 2, MRF Building, Rear 50 Murray Street, Perth, WA 6000, Australia. Tel: +61892240223; fax: +61892240204; e-mail: martyn.french@uwa.edu.au

Received 14 September, 2013

Revised 10 January, 2014

Accepted 10 January, 2014

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© 2014 Lippincott Williams & Wilkins, Inc.