Role of interleukin-12 in AIDS pathogenesis

Interleukin-12 (IL-12) is a disulfide-linked heterodimeric cytokine of 70 kDa formed by a heavy chain of 40 kDa (p40) and a light chain of 35 kDa (p35). Monocyte/macrophages are the physiologically most relevant producers of IL-12, in response to both Gram-positive and Gram-negative bacteria, bacterial products and intracellular parasites. Although IL-12 has an enhancing effect on the survival and growth of early hematopoietic progenitor cells, most of IL-12 biological activity has been described on T and natural killer (NK) cells, where it induces production of cytokines, primarily interferon (IFN)-γ, enhances cytotoxic activity and, in cooperation with other stimuli, increases proliferation. IL-12 induces development of T helper type 1 (Th1) cells and the equilibrium between IL-12 and IL-4 is probably important for the balance in vivo between Th1 and Th2 responses. IL-12 plays an important role in host resistance to infection, in particularly to intracellular pathogens, by activating macrophages through induction of IFN- γ from T and NK cells and by enhancing cell-mediated immune responses dependent on Th1 cell development. IL-12 is also an effective adjuvant in vaccines thus favoring the development of protective Th1 memory responses. The ability of peripheral blood mononuclear cells (PBMC) from HIV- seropositive individuals to produce IL-12 is impaired in response to bacterial stimulation, and IL-12 has been shown to restore some of these depressed immunological functions in vitro, suggesting that a defect in IL- 12 production may have a pathogenic role in the immunodeficiency of HIV- infected individuals. Based on these observations, phase I trials in HIV patients have shown modest tolerable toxicity and phase II trials will be initiated soon.