The immunologic consequences of HIV infection are loss of T helper and effector cell functions and severe reduction of CD4 T cell numbers. Because circulating HIV consists mainly of viral particles that are not productively infectious (>99%), we investigated whether HIV rendered noninfections by Aldrithiol-2 treatment (AT-2 HIV) would bind CD4 plasmacytoid dendritic cells (pDC) and/or T cells resulting in selective apoptosis of CD4 T cells and loss of T helper(CD4) and effector (CD8) cell function. Our findings indicate that, upon 24-hr exposure to AT-2 HIV, pDC produce interferon-alpha (IFN-alpha) and indoleamine 2,3-dioxygenase (IDO). IFN-alpha is essential for inducing TNF-Related Apoptosis-Inducing Ligand (TRAIL) on CD4 T cells, and AT-2 HIV induces TRAIL death receptor 5 (DR5) on CD4 T cells, resulting in their apoptosis. This mechanism has been suggested to be important for eliminating HIV-infected CD4 T cells. IDO catabolizes tryptophan, resulting in functional inhibition of both CD4 CD8 T cells. The CD4 T cells are blocked at or near the G1-S transition phase of the cellcycle, whereas the CD8 T cells are blocked from entering the cell cycle. This inhibition could reduce the activated CD4 T cell target pool for HIV-1 infection. However, because the great majority of circulating HIV is noninfectious, there is a higher statistical probability that HIV-CD4 binding events will be noninfectious and will kill and disarm otherwise healthy T cells, we hypothesize that the net effect of these HIV-hijacked immune regulatory mechanisms will be immunopathogenic and advantageous for the virus. Much of our in vitro data are supported by ex vivo studies involving patient blood and lymphoid tissue.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009267-25
Application #
7592600
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
25
Fiscal Year
2007
Total Cost
$1,187,652
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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