Baseline markers of inflammation and coagulation have been shown to be powerful predictors of adverse outcomes in patients with HIV infection. In a study of South African patients with advanced HIV infection baseline levels of C-reactive protein, interleukin-6 and D-dimer were found to be higher than that in comparable US populations and strongly associated with an increased risk of death. IL-15 is a cytokine involved in the regulation of the immune system with particularly striking effects on the proliferation and activation of NK and CD8 T cells. The IL-15 receptor utilizes its own unique alpha chain and the same beta- and gamma-chains as IL-2. To prepare for human trials in patients with HIV infection, recombinant human IL-15 was produced under conditions of good manufacturing practices (GMP). In a study of rhesus macaques randomized to control, IV bolus or continuous infusion IL-15 for 10 days, continuous infusion was associated with a 100-fold expansion of effector memory CD8+ T cells. HIV-induced immune activation is associated with an expansion of a subset of human CD8+ T cells expressing HLA-DR antigens. These cells have often been described as exhausted and dysfunctional. A detailed study of these cells in HIV patients and HIV uninfected controls revealed that these cells have a restricted T cell receptor repertoire, show evidence of having undergone multiple rounds of cell division despite not having recently engaged their T cell receptors and contain an increased fraction of cells actively proliferating in vivo. No qualitative differences were noted in CD8+HLA-DR+T cells between healthy controls and patients with HIV infection. These data indicate that this population of cells is a part of normal immune regulation that is exaggerated, but not dysfunctional, in the setting of HIV infection.
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