Regenerative granulopoietic failure is common in patients infected by HIV-1, a phenomenon we and others have attributed to dysfunction of HIV-1-infected bone marrow accessory cells; microvascular endothelial cells and mononuclear phagocytes in particular.(1) We have found that HIV-1 infected bone marrow stromal cells (infected ex-vivo or in-vivo) are less supportive of granulocyte-macrophage progenitor cell (CFU-GM) survival in co-cultures and, after stimulation with IL-1 produce significantly lower amounts of IL-6, GM-CSF and G-CSF than do uninfected stromal cells. We have also found that while infected stromal cells have a reduced capacity to support granulopoiesis, they are more supportive of growth/survival of lymphoma cells with the germinal center phenotype. Using vesicular stomatitis virus-G (VSV-G) pseudotyped HIV-1 vectors with inactivating mutations of various HIV-1 regulatory/accessory genes to transduce normal bone marrow stromal cells, we have determined that the two suppressive effects of HIV-1 on granulopoietic support function require HIV-1 vpr.
The aims of this proposal are designed to test the hypothesis that HIV-1 vpr is necessary and sufficient to account for the observed changes in hematopoietic support function of bone marrow stroma.
Our first aim i s to identify the molecular points of suppression of GM-CSF, G-CSF, and IL-6 gene expression by HIV-1 and HIV-1 vpr and to determine whether induction of these factors by TNF-alpha and CD40 ligand (CD40L) is similarly suppressed.
Our second aim i s to test the cause-and-effect relationship between GM-CSF, IL-6 and G-CSF inhibition and the inhibitory effects of HIV-1-infected bone marrow stromal cells on survival of CFU-GM.
Our third aim i s to use both retroviral mediated gene transfer of and tet-responsive vectors expressing HIV-1 vpr and other accessory proteins to determine the sufficiency of HIV-1 vpr in; (a) blunting bone marrow stromal cell responses to IL-1 (and other inducing factors including CD40L and TNF-alpha), (b) reducing the capacity of stroma to support CFU-GM, and (c) enhancing the survival of lymphoma cells with the germinal center phenotype. Results of these studies should clarify the molecular pathogenesis of regenerative granulopoietic failure in HIV-1 seropositive patients and may also reveal determinants of lymphoma progression in this clinical context.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK049887-07
Application #
6177359
Study Section
Special Emphasis Panel (ZRG1-AARR-2 (01))
Program Officer
Rankin, Tracy L
Project Start
1994-09-30
Project End
2004-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
7
Fiscal Year
2000
Total Cost
$338,877
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Moses, A; Nelson, J; Bagby Jr, G C (1998) The influence of human immunodeficiency virus-1 on hematopoiesis. Blood 91:1479-95
Moses, A V; Williams, S E; Strussenberg, J G et al. (1997) HIV-1 induction of CD40 on endothelial cells promotes the outgrowth of AIDS-associated B-cell lymphomas. Nat Med 3:1242-9
Moses, A V; Williams, S; Heneveld, M L et al. (1996) Human immunodeficiency virus infection of bone marrow endothelium reduces induction of stromal hematopoietic growth factors. Blood 87:919-25