Two important but unresolved issues in HIV/AIDS research are: 1] immune protection; and 2] immune dysregulation. This laboratory is involved in research that addresses both of these problems. Immune protection: The fact that vertical transmission occurs in only 25% of newborns of HIV-infected mothers (in the absence of anti-viral drug therapy) indicates that 75% of newborns escape infection, despite 9 months of intimate exposure to HIV-1. This observation suggests that some form of protection prevents the majority of fetuses and neonates from vertical infection by the AIDS virus. Our previous research indicated that stimulation of blood leukocytes with allogeneic (foreign) leukocytes generated a soluble factor (alloantigen-stimulated factor ? ASF) that inhibits HIV-1 replication. Since pregnancy is the primary setting in which recognition of HLA alloantigens occurs in nature, we hypothesized that our observation provides a mechanism by which neonates escape vertical transmission from their mothers. Our recent findings indicate that: 1] fetal cord blood can generate ASF when exposed to allogeneic adult blood leukocytes (Pinto et al. AIDS, 2003); 2] the major component of ASF anti-viral activity is due to the ribonuclease (RNase) eosinophil-derived neurotoxin (EDN) that is activated by alloantigen stimulation (allostimulation) (Rugeles et al. AIDS, 2003); 3] allostimulated EDN is produced by monocytes, but not by T lymphocytes or macrophages; 4] allostimulation results in activation of the EDN, RNase A and angiogenin genes, although we detect only EDN protein; and 5] ASF also inhibits HTLV-1 replication. This research may provide insights for a mechanism of natural protection against HIV-1, HTLV-1 and possibly other vertically-transmitted infectious diseases. Immune dysregulation: The mechanisms responsible for the selective depletion of CD+ T cells in progression to AIDS are still not fully understood. More than 95% of HIV-1 particles in blood are noninfectious, and too few CD4+ T lymphocytes are HIV-1 infected to account for the AIDS-associated severe depletion of T helper cells solely by an infectious mechanism. Therefore, we studied the effects of HIV-1 that had been chemically inactivated with Aldrithol-2 (AT-2 HIV-1) on the apoptotic death of CD4+ and CD8+ T cells from HIV-1-uninfected blood bank donors. Our results indicate that a 6-day exposure to AT-2 HIV-1 resulted in apoptosis in only 25-30% of CD4 and 10-20% of CD8+ T cells. Exposure to AT-2 HIV-1 induced gene expression and membrane-bound TNF-related apoptosis-inducing ligand (TRAIL - an apoptotic death molecule) on CD4+ but not on CD8+ T cells. Furthermore, TRAIL death receptors (DR) were not expressed on either subset. However, coculture with AT-2 HIV-1 and infectious influenza A virus (FLU) or measles resulted in selective apoptosis of CD4+ T cells (40-50% in 24 hours and 90-95% in 6 days), but only in 10-20% of CD8+ T cells. This apoptosis was associated with gene expression and detection of the DR5 death receptor on CD4+ but not on CD8+ T cells. In contrast, CD8+ T cells expressed the protective TRAIL decoy receptor, DcR1, when exposed to FLU. Apoptosis was strongly inhibited by antibodies against type 1 interferon, soluble CD4, or gp120, and was partly inhibited by soluble DR5 or antibody against TRAIL. Further investigation revealed that exposure to AT-2 HIV-1 resulted in upregulation of CTLA-4, which induced expression of indoleamine 2,3-dioxygenase (IDO) on CD4+ but not CD8+ T cells. IDO is the rate-limiting enzyme that catabolizes tryptophan, an essential amino acid that is required for T cell survival. These results provide two models in which noninfectious HIV-1 can induce selective apoptotic death of CD4+ T cells.
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