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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041937-03
Application #
3242930
Study Section
Special Emphasis Panel (SRC (DB))
Project Start
1989-06-01
Project End
1991-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
New York Blood Center
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065
Migliaccio, A R; Jiang, Y; Migliaccio, G et al. (1994) GATA-1-independent regulation of the expression of the erythropoietin receptor (EPO-R) gene in a human EPO-dependent cell line, UT-7 EPO. Ann N Y Acad Sci 718:359-61
Migliaccio, A R; Migliaccio, G; Adamson, J W (1994) Expansion of human neonatal progenitor cells in vitro under serum-deprived conditions. Blood Cells 20:424-8;discussion 428-9
Barron, C; Migliaccio, A R; Migliaccio, G et al. (1994) Alternatively spliced mRNAs encoding soluble isoforms of the erythropoietin receptor in murine cell lines and bone marrow. Gene 147:263-8
Migliaccio, A R; Baiocchi, M; Durand, B et al. (1994) Stem cell factor and the amplification of progenitor cells from CD34+ cord blood cells. Blood Cells 20:129-38;discussion 138-9
Durand, B; Eddleman, K; Migliaccio, A R et al. (1993) Long-term generation of colony-forming cells (CFC) from CD34+ human umbilical cord blood cells. Leuk Lymphoma 11:263-73
Shimada, Y; Migliaccio, G; Ralph, H et al. (1993) Erythropoietin-specific cell cycle progression in erythroid subclones of the interleukin-3-dependent cell line 32D. Blood 81:935-41
Migliaccio, A R; Migliaccio, G; Durand, B et al. (1993) The generation of colony-forming cells (CFC) and the expansion of hematopoiesis in cultures of human cord blood cells is dependent on the presence of stem cell factor (SCF). Cytotechnology 11:107-13
Migliaccio, A R; Jiang, Y; Migliaccio, G et al. (1993) Transcriptional and posttranscriptional regulation of the expression of the erythropoietin receptor gene in human erythropoietin-responsive cell lines. Blood 82:3760-9
Migliaccio, A R; Baiocchi, M; Durand, B et al. (1993) Aspects of the biology of the neonatal hematopoietic stem cell. Stem Cells 11 Suppl 2:56-64
Migliaccio, A R; Migliaccio, G; Mancini, G et al. (1993) Induction of the murine ""W phenotype"" in long-term cultures of human cord blood cells by c-kit antisense oligomers. J Cell Physiol 157:158-63

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