Almost all of HIV-induced T cell death in vitro involves direct loss of infected cells rather than indirect effects on uninfected bystander cells. DB07268 These results suggest that HIV-1 induces direct apoptosis of infected cells and kills T cells by a Fas-independent mechanism. Despite significant improvements in our understanding of the pathogenesis of AIDS, the mechanism by which human being immunodeficiency computer virus 1 (HIV-1) illness induces CD4+ T lymphocyte depletion is not known. Recent studies show that turnover of both HIV-1 and CD4+ T cells is extremely rapid (1C3) and that the viral weight soon after illness predicts the pace of CD4+ T cell loss and the development of AIDS (4). These observations suggest that active HIV-1 replication drives the loss of CD4+ T lymphocytes. However, there are important gaps in our knowledge of how HIV-1 causes this loss of T cells. The fundamental issue of whether HIV-1 mainly kills infected cells or induces death of uninfected cells remains controversial. This argument was initially prompted by the low rate of recurrence of HIV-infected cells recognized in vivo, which led to a search for indirect causes of T cell depletion (5). Indirect mechanisms of bystander T cell death could include the following: syncytium formation between infected and uninfected cells; aberrant T cell signaling due to binding of free gp120 to CD4 and cross-linking by anti-gp120 antibodies; triggering of apoptotic pathways in uninfected cells by soluble HIV-1 gene products DB07268 or by infected macrophages expressing Fas ligand; or cytokine dysregulation, such as overproduction of TNF-, leading to T cell death (5C7). However, given the quick turnover of CD4+ T cells, it is possible that direct killing by HIV-1 prospects to depletion without requiring that a high percentage of cells become productively infected at any given point in time. Therefore, to understand the pathogenesis of AIDS, it is important to know the degree to which HIV-induced T cell death involves direct loss of infected cells versus indirect killing of uninfected bystander cells. The process by which cells die offers generally been divided into apoptosis and necrosis based upon morphologic and biochemical criteria. There is accumulating evidence that T cell apoptosis is definitely improved in individuals with HIV-1 illness. PBMCs from HIV-infected individuals undergo apoptosis in tradition or after activation at a higher rate than PBMCs from uninfected settings (8C10). Improved apoptosis is also seen in lymph nodes from individuals with HIV-1 illness (11, 12). In animal models, improved T cell apoptosis is seen in SIV-infected macaques, which develop an AIDS-like syndrome, but not in HIV-infected chimpanzees, which hardly ever develop immunodeficiency (13, 14). However, in these studies both CD4+ and CD8+ T cells are affected (8, 13), raising the query of whether the improved apoptosis is directly due to HIV-1 illness or due to SPP1 indirect effects of the disease. The Fas/Fas ligand (FasL)1 system is a DB07268 key cellular apoptotic pathway that has been proposed to play a role in HIV-induced cell death (15). This pathway is definitely important in rules of lymphocyte survival and in antigen-induced T cell death (16). Since T cell activation augments HIV-induced apoptosis, the Fas pathway has been examined in individuals with HIV-1. Infected individuals have a higher percentage of Fas-expressing T cells as compared with uninfected people (17), and T cells from these individuals are more sensitive to killing by anti-Fas antibody.

Almost all of HIV-induced T cell death in vitro involves direct loss of infected cells rather than indirect effects on uninfected bystander cells