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 G0 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.

[1]  R. Lempicki,et al.  Interleukin‐2 induced immune effects in human immunodeficiency virus‐infected patients receiving intermittent interleukin‐2 immunotherapy , 2001, European journal of immunology.

[2]  M. Magnani,et al.  Abnormal intracellular kinetics of cell-cycle-dependent proteins in lymphocytes from patients infected with human immunodeficiency virus: a novel biologic link between immune activation, accelerated T-cell turnover, and high levels of apoptosis. , 2001, Blood.

[3]  C. Boucher,et al.  The Dominant Source of CD4+ and CD8+ T‐Cell Activation in HIV Infection Is Antigenic Stimulation , 2000, Journal of acquired immune deficiency syndromes.

[4]  H. Schuitemaker,et al.  T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock , 2000, Nature Immunology.

[5]  J. Kovacs,et al.  Pooled analysis of 3 randomized, controlled trials of interleukin-2 therapy in adult human immunodeficiency virus type 1 disease. , 2000, The Journal of infectious diseases.

[6]  J. Grooten,et al.  Interleukin-15 redirects the outcome of a tolerizing T-cell stimulus from apoptosis to anergy. , 2000, Blood.

[7]  J. Kahn,et al.  Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy: A randomized controlled trial. , 2000, JAMA.

[8]  S. Wittmer,et al.  Interferon γ Eliminates Responding Cd4 T Cells during Mycobacterial Infection by Inducing Apoptosis of Activated Cd4 T Cells , 2000, The Journal of experimental medicine.

[9]  C. Gioia,et al.  Decreased CD95 expression on naive T cells from HIV‐infected persons undergoing highly active anti‐retroviral therapy (HAART) and the influence of IL‐2 low dose administration , 2000, Clinical and experimental immunology.

[10]  P. Paoli,et al.  Effects of therapy with highly active anti‐retroviral therapy (HAART) and IL‐2on CD4+ and CD8+ lymphocyte apoptosis in HIV+ patients , 2000, Clinical and experimental immunology.

[11]  R Hoh,et al.  Factors influencing T-cell turnover in HIV-1-seropositive patients. , 2000, The Journal of clinical investigation.

[12]  G. Antonelli,et al.  Low-dose IL-2 reduces lymphocyte apoptosis and increases naive CD4 cells in HIV-1 patients treated with HAART. , 2000, Clinical immunology.

[13]  H. Pollard,et al.  Molecular dissection of nucleolin's role in growth and cell proliferation: new insights , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  M. Gersten,et al.  Reduction in T cell apoptosis in patients with HIV disease following antiretroviral therapy. , 1999, Clinical immunology.

[15]  M. Magnani,et al.  Unscheduled cyclin B expression and p34 cdc2 activation in T lymphocytes from HIV-infected patients. , 1999, AIDS.

[16]  M. Battegay,et al.  Downregulation of Bcl-2, but not of Bax or Bcl-x, is associated with T lymphocyte apoptosis in HIV infection and restored by antiretroviral therapy or by interleukin 2. , 1999, AIDS research and human retroviruses.

[17]  Gougeon,et al.  Activation, survival and apoptosis of CD45RO+ and CD45RO− T cells of human immunodeficiency virus‐infected individuals: effects of interleukin‐15 and comparison with interleukin‐2 , 1999, Immunology.

[18]  S. Kornbluth,et al.  All aboard the cyclin train: subcellular trafficking of cyclins and their CDK partners. , 1999, Trends in cell biology.

[19]  K. Debatin,et al.  Early effects of antiretroviral combination therapy on activation, apoptosis and regeneration of T cells in HIV-1-infected children and adolescents. , 1999, AIDS.

[20]  A. Lanzavecchia,et al.  From TCR Engagement to T Cell Activation A Kinetic View of T Cell Behavior , 1999, Cell.

[21]  M. Prins,et al.  Low T‐cell responses to CD3 plus CD28 monoclonal antibodies are predictive of development of AIDS , 1998, AIDS.

[22]  W. Fiers,et al.  Quiescence-inducing and antiapoptotic activities of IL-15 enhance secondary CD4+ T cell responsiveness to antigen. , 1998, Journal of immunology.

[23]  E. Vittinghoff,et al.  Diminished spontaneous apoptosis in lymphocytes from human immunodeficiency virus-infected long-term nonprogressors. , 1998, The Journal of infectious diseases.

[24]  S. Sieg,et al.  Role of the Fas/Fas Ligand Apoptotic Pathway in Human Immunodeficiency Virus Type 1 Disease , 1998, Journal of Virology.

[25]  V. Calvez,et al.  Susceptibility of peripheral blood mononuclear cells to apoptosis is correlated to plasma HIV load. , 1998, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[26]  M. Giacca,et al.  Effects of subcutaneous interleukin-2 therapy on CD4 subsets and in vitro cytokine production in HIV+ subjects. , 1997, The Journal of clinical investigation.

[27]  D. Hernandez-Verdun,et al.  Amount of the two major Ag-NOR proteins, nucleolin, and protein B23 is cell-cycle dependent. , 1997, Cytometry.

[28]  A. Lentsch,et al.  Distinct biological activities of recombinant forms of human interleukin-2 in vivo , 1997, Cancer Immunology, Immunotherapy.

[29]  Stephen J. Elledge,et al.  Cell Cycle Checkpoints: Preventing an Identity Crisis , 1996, Science.

[30]  Y. Adachi,et al.  IL-2 rescues in vitro lymphocyte apoptosis in patients with HIV infection: correlation with its ability to block culture-induced down-modulation of Bcl-2. , 1996, Journal of immunology.

[31]  J. Metcalf,et al.  Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. , 1996, The New England journal of medicine.

[32]  L. Montagnier,et al.  Programmed cell death in peripheral lymphocytes from HIV-infected persons: increased susceptibility to apoptosis of CD4 and CD8 T cells correlates with lymphocyte activation and with disease progression. , 1996, Journal of immunology.

[33]  D. Weissman,et al.  Immunopathogenic Mechanisms of HIV Infection , 1996, Annals of Internal Medicine.

[34]  C. Smith,et al.  Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals , 1995, The Journal of experimental medicine.

[35]  A. Fauci,et al.  Analysis of apoptosis in lymph nodes of HIV-infected persons. Intensity of apoptosis correlates with the general state of activation of the lymphoid tissue and not with stage of disease or viral burden. , 1995, Journal of immunology.

[36]  M. Roos,et al.  T cell function in vitro is an independent progression marker for AIDS in human immunodeficiency virus-infected asymptomatic subjects. , 1995, The Journal of infectious diseases.

[37]  T. Curiel,et al.  Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes , 1995, Nature Medicine.

[38]  A. Perelson,et al.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection , 1995, Nature.

[39]  Martin A. Nowak,et al.  Viral dynamics in human immunodeficiency virus type 1 infection , 1995, Nature.

[40]  R. Baserga.  Oncogenes and the strategy of growth factors , 1994, Cell.

[41]  F. Barré-Sinoussi,et al.  Programmed cell death and AIDS: significance of T-cell apoptosis in pathogenic and nonpathogenic primate lentiviral infections. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Rodgers,et al.  Anergy and apoptosis in CD8+ T cells from HIV-infected persons. , 1994, Journal of immunology.

[43]  M. Gurney,et al.  HIV type 1 infection of CD4+ T cells depends critically on basic amino acid residues in the V3 domain of envelope glycoprotein 120. , 1994, AIDS Research and Human Retroviruses.

[44]  H. Flad,et al.  Detection of intracellular interleukin 2: evidence for novel immunologically related forms of the lymphokine. , 1994, Cytokine.

[45]  F. Caprilli,et al.  Apoptosis in HIV infection: protective role of IL-2. , 1994, Journal of biological regulators and homeostatic agents.

[46]  F. Miedema,et al.  Programmed death of T cells in human immunodeficiency virus infection. No correlation with progression to disease. , 1994, The Journal of clinical investigation.

[47]  M. Schwartz,et al.  A transglutaminase that converts interleukin-2 into a factor cytotoxic to oligodendrocytes. , 1993, Science.

[48]  F. Miedema,et al.  Programmed death of T cells in HIV-1 infection. , 1992, Science.

[49]  P. Nurse,et al.  Coupling M phase and S phase: Controls maintaining the dependence of mitosis on chromosome replication , 1991, Cell.

[50]  義和 川上,et al.  The nucleolar organizer regions. , 1989, Biology of the cell.

[51]  Jaap,et al.  Immunological abnormalities in human immunodeficiency virus (HIV)-infected asymptomatic homosexual men. HIV affects the immune system before CD4+ T helper cell depletion occurs. , 1988, The Journal of clinical investigation.

[52]  R. Grant,et al.  Increased production of IL-7 accompanies HIV-1–mediated T-cell depletion: implications for T-cell homeostasis , 2001, Nature Medicine.

[53]  F Miedema,et al.  T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). , 2000, Blood.

[54]  A. Haase,et al.  Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. , 1999, Annual review of immunology.

[55]  W. Baumeister,et al.  The 26S proteasome: a molecular machine designed for controlled proteolysis. , 1999, Annual review of biochemistry.

[56]  A. Lanzavecchia,et al.  From TCR Engagement to Minireview T Cell Activation: A Kinetic View of T Cell Behavior , 1999 .

[57]  N. Tuteja,et al.  Nucleolin: a multifunctional major nucleolar phosphoprotein. , 1998, Critical reviews in biochemistry and molecular biology.

[58]  M. Lenardo.  Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. , 1991, Nature.

[59]  J. Underwood,et al.  Pathology of the Nucleus , 1990, Current Topics in Pathology.

[60]  T. Mustelin,et al.  Two phases of ornithine decarboxylase activation during lymphocyte mitogenesis. , 1988, Advances in experimental medicine and biology.