Thrombopoietin (TPO) has recently been discovered and is a potent regulator of both megakaryocyte progenitor proliferation and terminal megakaryocyte maturation. In vivo studies in rodent and subhuman primate models demonstrate that TPO can markedly increase circulating platelet numbers and restore megakaryocytopoiesis following suppressive treatment with x-irradiation and/or chemotherapy. Interestingly, TPO was also able to augment platelet production following treatment of rodents with antiplatelet antibodies, a model for immune thrombocytopenia. TPO is thus an attractive potential growth factor therapy for HIV-associated thrombocytopenia. The investigators propose to pursue in vitro biological studies of TPO as a framework for initial clinical studies in HIV-infected patients with sever thrombocytopenia. Three different in vitro culture systems will be employed to assess the mechanisms of HIV suppression of megakaryocyte progenitor and progeny development, and to determine the effects of TPO alone and in conjunction with other growth factors and/or anti-HIV agents. The preliminary data demonstrate in such culture systems a potent suppressive effect of prototype HIV isolates on in vitro megakaryocytopoiesis. The effects of TPO on HIV replication, interactions between HIV-infected T cells and monocyte-macrophages with developing megakaryocytes, relative dosing information, and the role of inhibitory cytokines such as TNF-alpha and TGF-beta may be derived from studies in these in vitro model systems. Furthermore, the effects of TPO on a specific strategy of HIV gene therapy, utilizing adeno-associated virus vectors, will be addressed. A prototype phase I safety and hematological efficacy trial of recombinant human TPO in severe HIV- associated thrombocytopenia is presented with intensive laboratory studies aimed at characterizing the effects of this growth factor on megakaryocytopoiesis and on HIV replication in vivo. By linking in vitro studies utilizing newly developed liquid culture systems of human megakaryocytes with a phase I clinical trial, the investigators aim to develop insights into optimal clinical applications of TPO in the HIV- infected host.
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