The overall goals of the proposal are to characterize the hematopoietic defects associated with human immunodeficiency virus (HIV) infection in man. These defects have limited the ability to treat the acquired immunodeficiency syndrome (AIDS) with drugs such as azidothymidine (AZT). Specifically, we propose to determine the sensitivity to recombinant human hematopoietic growth factors of marrow progenitor cells obtained from normal subjects, patients who are HIV-antibody-positive but who do not yet have AIDS, and patients with AIDS or AIDS-related complex (ARC). As part of the study, we will establish adherent cell layers from marrow aspirates obtained from the various study groups and determine the ability of these layers to support hematopoiesis in vitro and to respond to inflammatory modulators such as interleukin-1 (IL-1) by the production of specific hematopoietic growth factors. In addition, using in situ hybridization techniques, we will determine if the stromal cells of the adherent marrow cells are infected by HIV. Similarly, we will determine whether hematopoietic progenitor cells are also productively infected by HIV. We will examine the effect of therapeutic drugs such as AZT and related compounds for their effect on hematopoietic progenitor cell growth in an attempt to explain the selectivity of the erythroid suppression exerted by AZT. We also will attempt to reverse the AZT effect through the addition of hematopoietic growth factors in vitro and by adding compounds such as orotic acid to culture to bypass the AZT-imposed cell defect. Finally, we will explore the mechanisms of interaction between AZT and acetominophen, a compound which enhances AZT toxicity. From such studies, we hope to understand the mechanisms underlying marrow suppression in AIDS and how AZT exacerbates marrow failure. Through such understanding may come strategies for reducing the frequency and severity of marrow failure in drug-treated patients.
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