Interleukin-7 treatment counteracts IFN-α therapy-induced lymphopenia and stimulates SIV-specific cytotoxic T lymphocyte responses in SIV-infected rhesus macaques

• Published in: Blood 2010-12, Vol.116 (25), p.5589-5599
• Main Authors: Parker, Raphaëlle, Dutrieux, Jacques, Beq, Stéphanie, Lemercier, Brigitte, Rozlan, Sandra, Fabre-Mersseman, Véronique, Rancez, Magali, Gommet, Céline, Assouline, Brigitte, Rancé, Iann, Lim, Annick, Morre, Michel, Cheynier, Rémi
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - therapeutic use; Biological and medical sciences; Flow Cytometry; Hematologic and hematopoietic diseases; Hepatitis C virus; Human immunodeficiency virus; Humans; Immunologic Memory; Interferon-alpha - therapeutic use; Interleukin-7 - therapeutic use; Life Sciences; Lymphocyte Activation - drug effects; Lymphopenia - chemically induced; Lymphopenia - drug therapy; Macaca mulatta; Medical sciences; Other diseases. Hematologic involvement in other diseases; Simian Acquired Immunodeficiency Syndrome - drug therapy; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Immunodeficiency Virus - immunology; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes, Cytotoxic - immunology; Viral Load
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-03-276261

Interferon-α (IFN-α)–based therapy is presently the standard treatment for hepatitis C virus (HCV)–infected patients. Despite good effectiveness, this cytokine is associated with major side effects, including significant lymphopenia, that limits its use for HIV/HCV-coinfected patients. Interleukin-7 (IL-7) has recently shown therapeutic potential and safety in several clinical trials designed to demonstrate T-cell restoration in immunodeficient patients. The purpose of this study was to evaluate, in simian immunodeficiency virus-infected rhesus macaques, the relevance of IL-7 therapy as a means to overcoming IFN-α–induced lymphopenia. We showed that low-dose IFN-α treatment induced strong lymphopenia in chronically infected monkeys. In contrast, high-dose IFN-α treatment stimulated IL-7 production, leading to increased circulating T-cell counts. Moreover, IL-7 therapy more than abrogated the lymphopenic effect of low-dose IFN-α. Indeed, the association of both cytokines resulted in increased circulating T-cell counts, in particular in the naive compartments, as a consequence of central and peripheral homeostatic functions of the IL-7. Finally, reduced PD-1 expression by memory CD8+ T cells and transient T-cell repertoire diversification were observed under IL-7 therapy. Our data strongly suggest that IL-7 immunotherapy will be of substantial benefit in the treatment of HIV/HCV coinfection and should enhance the likelihood of HCV eradication in poorly responding patients.