Impaired hematopoiesis is well described in HIV infection, but the molecular mechanisms of this phenomenon are not well understood. Several recent developments in HIV biology provide new opportunities to molecularly characterize how HIV may inhibit hematopoietic progenitor cells: the identification of chemokine co-receptors for HIV gp120; robust expression of the CXCR chemokine receptor on subsets of marrow progenitors; the ability of HIV gp120 to trigger downstream signaling via CXCR; the induction of apoptosis in certain cells upon CXCR activation; and the lack of significant infection of hematopoietic progenitors. Our primary hypothesis is that HIV gp1220 signaling via CXCR triggers hematopoietic progenitor apoptosis and amplifies the apoptotic effects of TNF. As a corollary, the level of CXCR4 and CD4 expression hypothesis of CXCR4-mediated apoptosis; further, HIV gp120 treatment of marrow progenitors increased caspase-3 activity, the pro-apoptotic molecules Bax and p53, and potentially apoptotic kinases like RAFTK/PYK2 and ERK1/2.
Three specific aims will be pursued to address our hypotheses: (1) to further characterize downstream apoptotic signaling pathways in hematopoietic progenitors when HIV gp120 binds to the CXCR4 receptors; (2) to delineate on a molecular level how HIV gp120 enhances the apoptotic effects on TNF on progenitors; (3) to assess susceptibility of different hematopoietic lineage progenitors to HIV gp120 apoptosis, and to study how CXCR4 antibodies and TNF receptor inhibitors may protect progenitors from HIV gp120 apoptosis. These experiments are designed to contribute new knowledge on HIV interaction with hematopoietic progenitors, and thereby help design rational strategies to restore effective blood cell production and immune competence.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL053745-07
Application #
6343542
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (05))
Program Officer
Thomas, John
Project Start
1994-09-30
Project End
2003-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
7
Fiscal Year
2001
Total Cost
$413,920
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02215
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