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

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Title: Assessing the Efficacy of Interleukin-7 as an Immunotherapeutic in the SIV+ Rhesus Macaque Model
Author: Leone, Amanda Kathleen
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 . [Keywords : HIV /AIDS ; SIV ; immunotherapy ; Interleukin -7 (IL -7 ) ; Rhesus Macaque]
URI: http : / /hdl .handle .net /2152 .5 /909
Date: 2010-01-12

Citation

Assessing the Efficacy of Interleukin-7 as an Immunotherapeutic in the SIV+ Rhesus Macaque Model. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /909 .

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