Secretion and Protects HIV-Specific

Human immunodeficiency virus (HIV)–specific CD4+ T cell cytokine secretion is characteristically weak during HIV infection, in part because HIV-specific CD4+ T cells undergo massive apoptotic deletion. Glucocorticoid-induced tumor necrosis factor (TNF) receptor family–related (GITR) protein triggering enhances murine antigen-specific T cell cytokine secretion by protecting T cells from apoptosis. Therefore, we investigated the impact of GITR triggering on HIV-specific CD4+ T cell cytokine secretion and on apoptosis of HIV-specific CD4+ T cells. In HIV-infected subjects, CD4+ T cell surface expression of GITR was greater than that in uninfected control subjects, and phytohemagglutinin induction of additional GITR expression was impaired. However, antibody triggering of GITR significantly increased HIV-specific CD4+ T cell expression of TNF-a and interferon (IFN)–g. The percentage increase in HIV-specific CD4+ T cell expression of TNF-a correlated directly with the absolute peripheral CD4+ T cell count. Furthermore, GITR triggering reduced the expression of intracellular activated caspase-3 in HIV-specific CD4+ T cells. Taken together, these data suggest that, despite abnormal GITR expression during HIV infection, GITR triggering enhances HIV-specific CD4+ T cell cytokine expression and protects HIV-specific CD4+ T cells from apoptosis. Apoptosis of CD4+ T cells is central to the pathogenesis of HIV disease. HIV-specific CD4+ T cells are prefer