HIV infection causes pathological consequences that extend far beyond CD4+ cell depletion, which include anemia, granulocytopenia, thrombocytopenia and myelodysplastic/hyperplastic alterations of bone marrow. We have developed the SCID-hu mouse as a means of assessing pathogenic mechanisms of HIV and therapeutic modalities to combat these pathogenic effects. The SCID-hu mouse bears a human hematopoietic organ (Thy/Liv) that harbors long-lived human hematopoietic progenitor cells and directs their differentiation through the T-lymphoid lineage. In addition, human pluripotent hematopoietic progenitor cells can be recovered from these implants, and can be induced to differentiate along the myeloid and erythroid lineages ex vivo, thus the SCID-hu mouse possesses characteristics of both human thymus and bone marrow. Our earlier studies have shown that HIV infection causes a loss of CD4+ thymocytes, and a decrease in the ability of CD34+ progenitor cells to form myeloid and erythroid colonies in response to cytokine stimulation ex vivo. However reconstitution of these differentiative processes can be induced by HAART. Furthermore, the inhibitory effects on myeloid and erythroid differentiation appear to be indirect. More recently we have found that infection of these implants is associated with an increase in expression of two cellular genes (IP-10 and MIG) which are known to inhibit hematopoietic colony formation by precursor cells. The studies proposed herein will employ the SCID-hu mouse system to address mechanisms involved in HIV-induced perturbation of hematopoiesis and explore ways to augment reconstitution in the context of HAART. We will do this by the following Specific Aims: 1) Explore means to increase reconstitution of thymopoiesis following HIV-induced depletion of CD4 cells; 2) Explore means to increase reconstitution of hematopoietic colony-forming activity following HIV infection; 3) Define the roles of IP-10 and MIG-1 in HIV-induced loss of colony forming activity; 4) Further explore indirect mechanisms which could lead to hematopoietic abnormalities in vivo. A greater understanding the mechanisms leading to these hematopoietic abnormalities may allow development of better therapies for the consequences of HIV disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036554-11
Application #
6839486
Study Section
Special Emphasis Panel (ZRG1-AARR-3 (02))
Program Officer
Bridges, Sandra H
Project Start
1994-08-01
Project End
2006-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
11
Fiscal Year
2005
Total Cost
$381,250
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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