Role of c-Mpl in HIV-1 Induced Cytopenias

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DESCRIPTION (provided by applicant): HIV-1 infection and HAART can lead to cytopenias affecting blood cell formation and immune responses in infected patients. The PI will utilize the SCID mouse transplanted with human fetal thymus and liver tissues (SCID-hu Thy/Liv) to study the mechanisms of HIV-1 and HAART induced multilineage hematopoietic inhibition and testing cytokines and drug therapies. The PI will focus this research investigation on the hematopoietic cytokine, thrombopoietin (Tpo) and its receptor (c-mpl) since they are important effectors of multilineage hematopoiesis. The c-mpl is primarily associated with differentiation of CD34+ cells into megakaryocytes. The Specific aims of the proposal are as following: (1) to determine hematopoietic revival effects of CD34+c-mpl+ versus CD34+c-mpl- cells obtained from HIV-1 infected SCID-hu mouse in the presence or absence of HAART, following re-engraftment and reconstitution of these CD34+ cell subsets in the Thy/Liv implants of SCID-hu recipients, (2) to determine the effects of cytokine treatment and HAART on the c-mpl expression and hematopoietic revival effects of CD34+c-mpl+ versus CD34+c-mpl- cells, and (3) to determine if engraftment of CD34+ cells transduced with a lentiviral vector carrying human c-mpl gene into the SCID-hu Thy/Liv implants and cytokine treatment will contribute to multilineage hematopoiesis in HIV-1 infection.