Exogenous interleukin-2 administration corrects the cell cycle perturbation of lymphocytes from human immunodeficiency virus-infected individuals

Human immunodeficiency virus (HIV)-induced immunodeficiency is characterize d by progressive loss of CD4+ T cells associated with functional abnormalit ies of the surviving lymphocytes. Increased susceptibility to apoptosis and loss of proper cell cycle control can be observed in lymphocytes from HIV- infected individuals and may contribute to the lymphocyte dysfunction of AI DS patients. To better understand the relation between T-cell activation, a poptosis, and cell cycle perturbation, we studied the effect of exogenous i nterleukin-2 (IL-2) administration on the intracellular turnover of phase-d ependent proteins. Circulating T cells from HIV-infected patients display a marked discrepancy between a metabolic profile typical of G. and a pattern of expression of phase-dependent proteins that indicates a more-advanced p osition within the cell cycle. This discrepancy is enhanced by in Nitro act ivation with ConA and ultimately results in a marked increase of apoptotic events. Conversely, treatment of lymphocytes with IL-2 alone restores the p hase-specific pattern of expression of cell cycle-dependent proteins and is associated with low levels of apoptosis. Interestingly, exogenous IL-2 adm inistration normalizes the overall intracellular protein turnover, as measu red by protein synthesis, half-life of newly synthesised proteins, and tota l protein ubiquitination, thus providing a possible explanation for the eff ect of IL-2 on the intracellular kinetics of cell cycle-dependent proteins. The beneficial effect of IL-2 administration is consistent with the possib ility of defective IL-2 function in vivo, which is confirmed by the observa tion that lymphocytes from HIV-infected patients show abnormal endogenous I L-2 paracrine/autocrine function upon in vitro mitogen stimulation. Overall these results confirm that perturbation of cell cycle control contributes to HIV-related lymphocyte dysfunction and, by showing that IL-2 administrat ion can revert this perturbation, suggest a new mechanism of action of IL-2 therapy in HIV-infected patients.