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 (greater than 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 cell cycle, whereas the CD8 T cells are blocked from entering the cell cycle. We have also reecently found that AT-2 HIV activates the programmed death ligand-1 (PDL-1, which inhibits T cell immune responses. These inhibitory mechanisms 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. We have also used the simian immunodeficiency virus model in rhesus macaque monkeys to confirm and study in more detail the effects of these HIV-induced immune- suppressive mechanims in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009267-26
Application #
7732941
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
2008
Total Cost
$758,393
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Herbeuval, Jean-Philippe; Nilsson, Jakob; Boasso, Adriano et al. (2009) HAART reduces death ligand but not death receptors in lymphoid tissue of HIV-infected patients and simian immunodeficiency virus-infected macaques. AIDS 23:35-40
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Herbeuval, Jean-Philippe; Shearer, Gene M (2007) HIV-1 immunopathogenesis: how good interferon turns bad. Clin Immunol 123:121-8
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Bedoya, Victoria I; Boasso, Adriano; Hardy, Andrew W et al. (2006) Ribonucleases in HIV type 1 inhibition: effect of recombinant RNases on infection of primary T cells and immune activation-induced RNase gene and protein expression. AIDS Res Hum Retroviruses 22:897-907

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