Anemia, granulocytopenia, lymphopenia, and thrombocytopenia are common in HIV infection though their pathogenesis is not well understood. Bone marrow hypoproliferation (ineffective hematopoiesis) is likely to be a main contributor to the etiology of these hematologic aberrations, and may be due to stem cell infection, or stromal cell infection with loss of a satisfactory microenvironment to support bone marrow growth. This growth is a complex process requiring primary and secondary colony stimulating factors, nutrients, and cell:cell contact. In addition, toxic, inhibitory, and immune factors must not be present if optimal hematopoiesis is expected. In studies of SIV infected rhesus macaques, we have described peripheral blood cytopenias, stage-related CFU-GM and BFU-E hypoproliferation, absence of infection in CD34+ progenitors, partial restoration of CFU growth with high doses of IL-3 and GM-CSF, and the presence of an inhibitor or rhesus bone marrow secreted by HIV infected H9 cells. These data show the similarity of SIV infected monkeys to HIV infected humans, suggest that ineffective hematopoiesis, with cytokinetic and possibly inhibitory abnormalities, is a factor and support the use of this model for studying the effects of cytokine administration. Herein, the investigators propose a comprehensive study of the hematologic an virologic consequences of exogenous cytokine administration in rhesus macaques experimentally infected with SIV. this model is advantageous as i (1) allows testing of animals (without concomitant antiviral therapy), (2) allows investigators to know the time of infection, (3) has a well-defined disease progression in the grant period, and (4) is supported by preliminary data which suggest that the hematologic consequences of SIV infection are very similar to those of HIV. Specifically, the investigators propose to study effects of exogenously administered cytokines on hematopoietic compartment expansion, sites of cellular infection, and viral replication and burden following cytokine administration. The investigators will utilize compartment specific cytokines, tested in monkeys infected with a lymphocyte or a monocyte predominate SIV strain. It is expected that, through these aims, the positive effects of cytokines in SIV infected macaques can be demonstrated, any untoward effects of cytokines on viral replication can be elucidated, and a model can be characterized for future cytokine, bone marrow transportation,and gene therapy experiments. The studies proposed herein will require the efforts of a team of investigators with extensive previous collaborations, experience, and expertise in the areas of hematopoietic, immunologic, and virologic aspects of SIV infection, and cytokine use in animal models.
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