Anemia, granulocytopenia, lymphopenia, and thrombocytopenia are common in HIV infection though the pathogenesis of these abnormalities is not well understood. Bone marrow hypoproliferation (ineffective hematopoiesis) is likely to be a main contributor, and may be due to 1) stem cell infection, or 2) stromal cell infection with a loss of satisfactory support for bone marrow growth. This growth is a complex process requiring colony stimulating factors, nutrients, and possibly, cell:cell contact/cytokines from cells in the bone marrow microenvironment. It is these factors - hematopoietic stem/progenitor cell infection, microenvironment, and cytokinetic support, that will be studied in this proposal. In studies of SIV-infected rhesus macaques, we have described peripheral blood cytopenias stage-related CFU-GM and BFU-E hypoproliferation, absence of infection in CD34+ progenitors, partial restoration of CFU growth with IL- 3 and GM-CSF, and the presence of an inhibitor of rhesus bone marrow secreted by HIV-infected H9 cells. These data show the similarity of SIV- infected monkeys to HIV-infected humans and suggest that ineffective hematopoiesis, with cytokinetic and inhibitory abnormalities, is a factor. We also have preliminary data to suggest: a) the mechanistic importance of the CD8+ """"""""facilitating"""""""" cell and CD69. b) suboptimal cytokine responses by the animals, and c) cytokine-induced increases in viral replication by cells infected with the monocytotropic isolate SIVmac239 17E. Herein, we propose a comprehensive study of the site, function, and mechanism of the hematologic, virologic, and immunologic consequences of SIV infection in 12 rhesus monkeys (4 controls, 4 infected with a lymphocytotropic isolate, and 4 infected with a predominately monocytotropic isolate). This model is advantageous as it l) allows serial testing of animals (where time of infection is known). 2) allows study of cell lineage specific SIV infection from in vivo infected samples, 3) has a well-defined disease progression in the grant period, and 4) is supported by preliminary data which suggest that: a) the hematologic consequences of SIV infection are very similar to those of HIV, b) the monocytotropic variant reacts differently and c) the mechanism of the abnormalities can be addressed in our system. Specifically, we propose to define the currently defined lineages of bone marrow cell types infected with SIV in highly enriched cell populations including CD34+ and stromal cells, determine their growth potential in short- and long-term cultures, and evaluate the mechanistic roles of cellular adhesion molecules, hematopoietic cytokines, and the putative """"""""facilitating"""""""" cell. As a group, we have developed the knowledge, reagents, assays, and the necessary expertise for reproducible studies with SIV-infected nonhuman primates. In addition to contributing to understanding the hematologic consequences of HIV infection and their attendant morbidity, the studies proposed herein may also lead to a foundation for cytokine, bone marrow transplant and gene transfer investigations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL053738-04
Application #
2901199
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Project Start
1996-04-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2001-03-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322