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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL053703-06
Application #
2771398
Study Section
Special Emphasis Panel (ZHL1-CSR-C (S1))
Project Start
1994-09-30
Project End
2001-08-31
Budget Start
1998-09-01
Budget End
2001-08-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Dallalio, Gail; Means Jr, Robert T (2003) Effects of oxidative stress on human erythroid colony formation: Modulation by gamma-interferon. J Lab Clin Med 141:395-400
Van Laer, A; Dallalio, Gail; McKenzie, Stacey W et al. (2002) Thioredoxin and protein nitrotyrosine in bone marrow supernatant from patients with human immunodeficiency virus infection. J Investig Med 50:10-8
Means Jr, R T (2000) The anaemia of infection. Baillieres Best Pract Res Clin Haematol 13:151-62
Dallalio, G; North, M; Worden, B D et al. (1999) Inhibition of human erythroid colony formation by ceramide. Exp Hematol 27:1133-8
Means Jr, R T (1999) Advances in the anemia of chronic disease. Int J Hematol 70:7-12
North, M; Dallalio, G; Donath, A S et al. (1997) Serum transferrin receptor levels in patients undergoing evaluation of iron stores: correlation with other parameters and observed versus predicted results. Clin Lab Haematol 19:93-7
Means Jr, R T (1997) Cytokines and anaemia in human immunodeficiency virus infection. Cytokines Cell Mol Ther 3:179-86
Means Jr, R T; Krantz, S B (1996) Inhibition of human erythroid colony-forming units by interferons alpha and beta: differing mechanisms despite shared receptor. Exp Hematol 24:204-8