The depletion of CD4+ T cells is the immunologic surrogate marker that defines the acquired immunodeficiency syndrome (AIDS). This loss of T helper cells has been attributed to the direct cytopathic effects resulting from infection with human immunodeficiency virus-type 1 (HIV-1). However, the decline in CD4+ T cell numbers in HIV-infected individuals is preceded by the loss of T helper cell function. The efforts of my laboratory are focused on a single project that is investigating immunopathogenic mechanisms that may contribute to the loss of T helper cell function and CD4+ T cell numbers that is observed in progression to AIDS. This project involves the development and study of two in vitro models of HIV-induced apoptosis and unresponsiveness of CD4+ T cells, and the testing of whether these models might contribute to the depletion of CD4+ T cells in HIV-infected patients. These two models are: 1) HIV-induced TNF-Related Apoptosis-Inducing Ligand (TRAIL)-mediated apoptosis of CD4+ T cells; and 2) HIV-induced indoleamine 2,3-dioxygenase (IDO)-mediated unresponsiveness of CD4+ T cells by tryptophan depletion leading to T lymphocyte tryptophan starvation. We initially chose these two models because recent reports have suggested that TRAIL may contribute to T cell death in HIV-infected patients, and CTLA-4, which can increase IDO expression, as well as IDO itself, is increased in HIV-infected patients. Our major scientific achievements in the TRAIL/DR5/apopotosis model include the following: 1) Exposure of PBMC or isolated T cells from HIV-seronegative donors to noninfectious or infectious HIV-1 induces apoptosis of CD4+ but not CD8+ T cells, and is due to the selective expression of TRAIL and TRAIL Death Receptor DR5 expression by CD4+ T cells. 2) Apoptosis is partly inhibited by anti-TRAIL and anti-DR5 antibodies, and is effectively inhibited by IFN-???}?O-specific antibodies. 3) Noninfectious as well as infectious HIV-1 activate plasmacytoid dendritic cells (pDC) to produce type I interferon, which induces TRAIL expression by CD4+ T cells, as well as increased STAT1 and STAT2, and their phosphorylation, which are required for TRAIL expression. 4) The binding of HIV-1 to CD4+ T cells appears to be required for expression of DR5. 6) The HIV-1/CD4 binding inhibitor, soluble CD4-IgG (sCD4-IgG), but not viral coreceptor ligands, completely inhibits HIV-1-induced apoptosis, TRAIL and type I interferon production. 7) The effects induced by infectious and noninfectious HIV-1 are indistinguishable. 8) Analyses of HIV-infected patients' plasma and PBMC indicate that TRAIL levels are elevated compared to controls. HAART induces a reduction in plasma TRAIL levels that parallel decreases in viral load, and also induces decreases in the DR5/CD4 mRNA ratio that inversely associates with increases in CD4 count. Our major scientific achievements in the The HIV-induced IDO/tryptophan depletion model include: 1) Exposure of PBMC to either CTLA-4 or HIV-1 results in expression of IDO (an enzyme that catabolizes tryptophan) in monocytes, and also tryptophanyl t-RNA synthetase (TTS), an enzyme that may protect free tryptophan from the IDO catabolism. 2) Distinct leukocyte subsets differentially express CTLA-4-induced IDO and TTS mRNA, such that CD4+ cells express more TTS than IDO, and more of both enzymes than do CD8+ cells. 3) Exposure of PBMC to infectious or noninfectious HIV-1 increases the expression of CTLA-4, B7.1, IDO, TTS, and changes the IDO/TTS ratio in favor of IDO. 4) CTLA-4- or HIV-1-induced upregulation of IDO is associated with the loss of CD4+ but not CD8+ T cell responses to PHA. 5) This effect is blocked by 1-methyl tryptophan, a competitive inhibitor of IDO function.
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