title: Exogenous interleukin-2 administration corrects the cell cycle perturbation of lymphocytes from human immunodeficiency virus-infected individuals.
abstract: Human immunodeficiency virus (HIV)-induced immunodeficiency is characterized by progressive loss of CD4(+) T cells associated with functional abnormalities 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 AIDS patients. To better understand the relation between T-cell activation, apoptosis, and cell cycle perturbation, we studied the effect of exogenous interleukin-2 (IL-2) administration on the intracellular turnover of phase-dependent proteins. Circulating T cells from HIV-infected patients display a marked discrepancy between a metabolic profile typical of G(0) and a pattern of expression of phase-dependent proteins that indicates a more-advanced position within the cell cycle. This discrepancy is enhanced by in vitro activation with ConA and ultimately results in a marked increase of apoptotic events. Conversely, treatment of lymphocytes with IL-2 alone restores the phase-specific pattern of expression of cell cycle-dependent proteins and is associated with low levels of apoptosis. Interestingly, exogenous IL-2 administration normalizes the overall intracellular protein turnover, as measured by protein synthesis, half-life of newly synthesised proteins, and total protein ubiquitination, thus providing a possible explanation for the effect of IL-2 on the intracellular kinetics of cell cycle-dependent proteins. The beneficial effect of IL-2 administration is consistent with the possibility of defective IL-2 function in vivo, which is confirmed by the observation that lymphocytes from HIV-infected patients show abnormal endogenous IL-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 administration can revert this perturbation, suggest a new mechanism of action of IL-2 therapy in HIV-infected patients.
authors.affiliation: Vaccine Research Center and Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30329, USA.
authors.forename: M
authors.initials: M
authors.lastname: Paiardini
authors.forename: D
authors.initials: D
authors.lastname: Galati
authors.forename: B
authors.initials: B
authors.lastname: Cervasi
authors.forename: G
authors.initials: G
authors.lastname: Cannavo
authors.forename: L
authors.initials: L
authors.lastname: Galluzzi
authors.forename: M
authors.initials: M
authors.lastname: Montroni
authors.forename: D
authors.initials: D
authors.lastname: Guetard
authors.forename: M
authors.initials: M
authors.lastname: Magnani
authors.forename: G
authors.initials: G
authors.lastname: Piedimonte
authors.forename: G
authors.initials: G
authors.lastname: Silvestri
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D002453:Cell Cycle / Q000187:drug effects*; D002466:Cell Nucleolus; D003546:Cysteine Endopeptidases / Q000096:biosynthesis; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects* / Q000502:physiology; D009097:Multienzyme Complexes / Q000096:biosynthesis; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D046988:Proteasome Endopeptidase Complex
chemical_list: D007376:Interleukin-2; D009097:Multienzyme Complexes; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D009955:Ornithine Decarboxylase