Abstract
The use of interleukin-7 (IL-7) as an immunorestorative therapeutic has proven effective in HIV infection, cancer and bone marrow transplantation. Mediating its activity through membrane-bound IL-7 receptor α (mCD127), IL-7 therapy increases T-cell numbers and survival. A soluble form, sCD127, is found in plasma, and we have previously identified increased plasma sCD127 concentrations in HIV infection. Furthermore, patients with high sCD127 exhibited the best viral control, implicating a role for IL-7 or sCD127 directly in improved virologic/immunologic outcomes. The role of the cytokine IL-7 in elevating sCD127 levels was addressed here through assessment of retrospective samples obtained from SIV-infected antiretroviral (ART)-treated Rhesus macaques. IL-7 was administered in clustered weekly doses, allowing for an assessment prior, during and following IL-7 administration. The levels of sCD127 remained relatively unchanged during both early SIV infection and following initiation of ART. However, treatment with IL-7 increased sCD127 concentrations in most animals, transiently or persistently, paralleling increased T-cell numbers, correlating significantly with CD8+ T-cell levels. In addition, proliferating CD4+ or CD8+ T-cells (measured by Ki67) increased in association with elevated sCD127 concentrations. Finally, a high concentration of sCD127 in IL7-treated animals was associated with increased retention of T-cells (measured by BrDU). In addition, a lack, or loss of viral control was associated with more pronounced and frequent elevations in plasma sCD127 concentrations with IL-7 therapy. In summary, plasma sCD127 levels in SIV-infected ART-treated macaques was associated with therapeutic IL-7 administration, with higher sCD127 levels in macaques demonstrating the best T-cell responses. This study furthers our knowledge regarding the interrelationship between increased IL-7 levels and elevated sCD127 levels that may have implications for future IL-7 immunotherapeutic approaches in HIV-infected patients.
Highlights
Interleukin-7 (IL-7) regulates the homeostasis of mature T-cells by inducing cell proliferation and promoting cell survival by altering the balance between pro- and anti- apoptotic proteins
The present study has found that plasma soluble CD127 (sCD127) concentrations parallel these outcomes in simian immunodeficiency virus (SIV)-infected, ART-treated Rhesus macaques administered IL-7
Repeated injections of IL-7 resulted in transiently increased concentrations of sCD127 that were affected by the degree of viral suppression in each animal
Summary
Interleukin-7 (IL-7) regulates the homeostasis of mature T-cells by inducing cell proliferation and promoting cell survival by altering the balance between pro- and anti- apoptotic proteins. Therapeutic administration of IL-7 has been evaluated for the treatment of cancer [6], chronic HIV infection[7, 8] and transplantation[9] in which T-cell reconstitution is required. Clinical trials conducted in bone-marrow transplant and cancer patients, indicated that IL-7 therapy increased T-cell expansion, survival, thymic output, and T-cell receptor repertoire diversity[14, 15]. Findings suggest that IL-7 immunotherapy has a net positive effect with regard to increasing T-cell numbers and survival[7, 8] and in SIV-infected Rhesus macaques, IL-7 therapy aided to overcome IFN-α treatment-induced lymphopenia[16]
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