Assessing the Efficacy of Interleukin-7 as an Immunotherapeutic in the SIV+ Rhesus Macaque Model

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2010-01-12

Authors

Leone, Amanda Kathleen

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Abstract

Human Immunodeficiency Virus (HIV) infection is known for depleting ‘helper’ CD4+ T cells. Highly active antiretroviral therapy (HAART) reduces viremia and increases CD4+ levels, however, 5-20% of patients fail to reconstitute CD4+ T cell levels despite viral suppression. Interluekin-7 (IL-7), a homeostatic cytokine, increases proliferation and survival of memory T cells. It is also a candidate immune therapeutic to assist CD4+ T cell recovery following HIV infection. Simian immunodeficiency virus (SIV) infection of Rhesus macaques, mimics the disease course of HIV patients and has been used to study HIV pathogenesis and treatment. The goal of this dissertation was to identify a strategy for administering IL-7 to SIV+ anti-retroviral therapy (ART) treated macaques to increase CD4+ T cell levels long-term. Glycosylated recombinant macaque IL-7 was given subcutaneously at 7 day to 6-week intervals. Proliferation, and levels, of naïve and memory CD4+ T cells, as well as other immune cell subsets were assessed. Irrespective of the dosing interval tested IL-7 transiently increased proliferation of memory and naïve cells, in CD4+ and CD8+ subsets without increasing plasma SIV titers. CD4+ T cells proliferated following each IL-7 administration at 6-week intervals, but absolute levels increased only transiently. In contrast, a frequent IL-7 dosing regimen (weekly x 3, with 2 weeks rest repeated twice) induced a single proliferative burst in CD4+ T cells but T cell levels were increased >112 days post IL-7 treatment. This strategy also increased the half-life of bromodeoxy-uridine (BrDU) labeled memory T cells in the blood when compared to ART alone, consistent with enhanced cell survival. Further, we show that untreated SIV+ macaques have attenuated proliferation compared to uninfected macaques (and ART treated macaques) with minimally increased T cell levels following IL-7. Additionally, chronic SIV infection is associated with impaired STAT5 activation, which may possibly decrease cell survival. These data suggest that administering IL-7 at frequent intervals in conjunction with ART is the optimal strategy to obtain sustained increases of memory CD4+ T cell levels. These findings in the SIV-macaque model provide evidence that IL-7 is a potentially broad acting immune therapeutic that could be administered to HIV+ patients that do not fully restore CD4+ T cell levels after HAART treatment.

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