DEVELOPMENT OF A JANUS KINASE 3 (JAK3) INHIBITOR FOR USE IN RHESUS MACAQUES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our previous data place CD4+ central memory T cells and the mechanisms that maintain the homeostasis of this population and regulate its differentiation into tissue homing effector memory at the center of AIDS pathogenesis. In rodent models, the major regulators of memory T cell homeostasis are the common gamma chain cytokines IL-7 and IL-15, and we and others have demonstrated that these cytokines have analogous activities in non-human primates. The role of these cytokines in the SIV infection-associated CD4+ memory production response described above is unknown. It is very likely that either or both of these cytokines play a major part in this crucial response, and therefore counter the development of immunodeficiency. On the other hand, it is also possible that these pro-proliferative cytokines support or increase SIV pathogenicity by their ability to induce production of target (substrate) cells for viral replication. Understanding the role of common gamma chain cytokines IL-7 and IL-15 in maintaining and regulating T-cell populations during SIV infection will be necessary to better understand both pathogenic mechanisms and the potential for exploiting this regulatory axis for therapeutic benefit. IL-7 and IL-15 receptors share a common gamma chain (hence, the name "common gamma chain cytokine family"), and the use of Janus Kinase 3 (JAK3) as an intracellular signaling mediator downstream of this common gamma chain. Pharmacologic inhibition of JAK3 would inhibit the activities of both IL-7 and IL-15 (as well as other common gamma chain cytokines such as IL-2, IL-4 and IL-21, which have more specialized functions), and allow us to globally assess the overall role of these cytokines in AIDS pathogenesis. The goal of this project is to assess the potential of the JAK3 inhibitor JANEX-1 as a tool for in vivo inhibition of IL-7 and IL-15 activity in rhesus macaques, and to provide preliminary data demonstrating the utility of this reagent for assessment of the role of the common gamma chain cytokine family in SIV pathogenesis.