This project is based on the hypothesis that the pathophysiology of anemia and granulocytopenia in acquired immunodeficiency syndrome (AIDS). AIDS related complex (ARC), and the treatment of these diseases, can involve abnormal hematopoietic progenitor cells, or alternatively an abnormal interaction between progenitor cells and human immunodeficiency virus(HIV) infected hematopoietic accessory cells (i.e., T cells and monocytes) or both.
The specific aims are to; 1) determine if drugs used in the treatment of HIV infection modulate proliferation and differentiation of erythroid and myeloid progenitor cells in vitro; 2) determine if hematopoietic growth factors can counteract inhibition of hematopoiesis by antiviral drugs; 3) determine the effect of in vivo drug therapy on in vitro hematopoiesis in patients with asymptomatic HIV infection, AIDS, and ARC; and 4) determine if impaired hematopoiesis in HIV infection is due to abnormally functioning erythroid and myeloid progenitor cells or impaired regulatory functions by HIV infected accessory cells (T-cells and monocytes), or both. Drugs used in the treatment of AIDS and ARC and hematopoietic growth factors will be added to cultures of bone marrow and/or peripheral blood of normal adults and HIV infected patients alone and in combination. The effects will be evaluated by counting progenitor cell derived colonies. Dose response curves will be generated for each drug tested. To determine if drugs exert their effects on early progenitors or later maturing hemopoietic cells, mononuclear cells (MNC) will be 'pulse' incubated with drugs prior to culture, or drugs will be added serially during the cultured period. To determine if drugs act directly on progenitor cells and/or via accessory cells, drugs will be added to MNC depleted of monocytes, T- cells, T-cell subsets, or combinations thereof. Synergistic effects of drug will be tested by adding combinations of drugs to cultures. Progenitor cells HIV infected patients participating in clinical trails will be cultured prior to, during and after treatment to assess the effect of in vivo treatment of progenitor and accessory cells. To determine if HIV infected T-cells and monocytes can perform normal accessory cell functions, MNC will be depleted of these cells and cultured alone and in combination with added accessory cells. The ultimate goal of these studies is to develop a better understanding of the etiology of anemia and granulocytopenia in AIDS and ARC, and to suggest appropriate therapies.
|Weinberg, R S; Chusid, E D; Galperin, Y et al. (1998) Effect of antiviral drugs and hematopoietic growth factors on in vitro erythropoiesis. Mt Sinai J Med 65:5-13|
|Weinberg, R S; Thomson, J C; Lao, R et al. (1993) Stem cell factor amplifies newborn and sickle erythropoiesis in liquid cultures. Blood 81:2591-9|
|Weinberg, R S; He, L Y; Alter, B P (1992) Erythropoiesis is distinct at each stage of ontogeny. Pediatr Res 31:170-5|