HEMATOPOIETIC SUPPRESSION IN HIV INFECTION

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Peripheral blood cytopenias are commonly found in infection with the human immunodeficiency virus (HIV). The cytopenias associated with HIV infection may affect the health of patients by increasing exposure to transfusions, by predisposing to bacterial infection or bleeding, or by limiting therapeutic options such as antiretroviral therapy. Suppression of hematopoiesis in HIV infection may result from infection of marrow accessory cells which support and regulate hematopoiesis, infection of hematopoietic progenitors themselves, or both. Antiretroviral therapy may exacerbate these effects. Extensive investigation has indicated that the cytokines mediating the immune response, such as interleukin-1, tumor necrosis factor, and the interferons, produce the anemia associated with chronic inflammatory disorders. These cytokine effects occur at several levels, including hematopoietic progenitor suppression and inhibition of appropriate growth factor production. The hypothesis to be tested in this proposal is that suppression of erythropoiesis in HIV infection results from the same mechanism, and that HIV infection itself may alter the susceptibility of hematopoietic progenitors to growth factors and cytokines. The hypothesis will be tested by determination of marrow cytokine levels in HIV-infected individuals; by assessment of cytokine/ growth factor responsiveness of hematopoietic progenitors from HIV patients relative to non-HIV infected individuals, including correction of cytokine mediated inhibition of erythropoiesis by hematopoietic growth factors; by evaluating the effects of antiretroviral agents on cytokine/growth factor responsiveness of hematopoietic progenitors from HIV patients relative to non-HIV infected individuals; and by determining the effects of antiretroviral agents on erythropoietin binding to highly purified human erythroid progenitors. The approach proposed in these studies will provide new insight into the mechanisms of hematopoietic suppression in HIV infection, and potentially direct research into therapeutic modalities resulting in enhanced quality of life for these patients.