Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: role of type I IFN-producing plasmacytoid dendritic cells.

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, was suggested to contribute to HIV-1 pathogenesis by inducing CD4+ T cell death characteristic of AIDS. We previously reported HIV-1-mediated, TRAIL-induced apoptosis in primary CD4+ T cells in vitro and observed elevated levels of plasma TRAIL in HIV-1-infected patients. The present study elucidates the unresolved mechanism by which HIV-1 induces TRAIL expression on primary CD4+ T cells. We demonstrate that the expression of TRAIL by primary CD4+ T cells is regulated by IFN-alpha that is produced by HIV-1-stimulated plasmacytoid dendritic cells (pDCs). We also found that IFN-induced TRAIL is mediated by signal transducers and activators of transcription 1 and 2. We show that IFN-alpha production by HIV-1-activated pDCs is blocked by an early viral entry inhibitor of CD4-gp120 binding, but not by inhibitors of viral coreceptor binding. Our in vitro data are supported by the demonstration that anti-IFN-alpha and -beta Abs inhibit apoptosis and TRAIL expression in CD4+ T cells from HIV-1-infected patients. Our findings suggest a potential unique role of pDCs in the immunopathogenesis of HIV-1 infection by inducing the death molecule TRAIL.

[1]  L. Arthur,et al.  Cholesterol Depletion of Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus with β-Cyclodextrin Inactivates and Permeabilizes the Virions: Evidence for Virion-Associated Lipid Rafts , 2003, Journal of Virology.

[2]  L. Hood,et al.  Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. , 1997, Immunity.

[3]  G. Trinchieri,et al.  Plasmacytoid dendritic cells in immunity , 2004, Nature Immunology.

[4]  L. Zitvogel,et al.  Dendritic cells in innate immune responses against HIV. , 2002, Current molecular medicine.

[5]  R. Zachoval,et al.  HIV antigen, HIV antibody and serum interferon in a patient with encephalopathy , 1987, Infection.

[6]  V Chams,et al.  Interferon alpha and Tat involvement in the immunosuppression of uninfected T cells and C-C chemokine decline in AIDS. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[7]  N. Kadowaki,et al.  The nature of the principal type 1 interferon-producing cells in human blood. , 1999, Science.

[8]  I. Herr,et al.  TRAIL/Apo‐2‐ligand‐induced apoptosis in human T cells , 1998, European journal of immunology.

[9]  S. J. Clark,et al.  High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. , 1993, Science.

[10]  K. Abel,et al.  The Relationship between Simian Immunodeficiency Virus RNA Levels and the mRNA Levels of Alpha/Beta Interferons (IFN-α/β) and IFN-α/β-Inducible Mx in Lymphoid Tissues of Rhesus Macaques during Acute and Chronic Infection , 2002, Journal of Virology.

[11]  O. Strannegard,et al.  Interferon-alpha and tumor necrosis factor-alpha in serum of patients in various stages of HIV-1 infection. , 1991, AIDS research and human retroviruses.

[12]  J. Levy,et al.  Natural type 1 interferon producing cells in HIV infection. , 2002, Human immunology.

[13]  R Blumenthal,et al.  Quantitation of human immunodeficiency virus type 1 infection kinetics , 1993, Journal of virology.

[14]  Yi-da Yang,et al.  Monocytes Treated with Human Immunodeficiency Virus Tat Kill Uninfected CD4+ Cells by a Tumor Necrosis Factor-Related Apoptosis-Induced Ligand-Mediated Mechanism , 2003, Journal of Virology.

[15]  Q. Sattentau,et al.  Inactivation of Human Immunodeficiency Virus Type 1 Infectivity with Preservation of Conformational and Functional Integrity of Virion Surface Proteins , 1998, Journal of Virology.

[16]  T. Taniguchi,et al.  Antiviral response by natural killer cells through TRAIL gene induction by IFN–α/β  , 2001, European journal of immunology.

[17]  Arul M. Chinnaiyan,et al.  The Receptor for the Cytotoxic Ligand TRAIL , 1997, Science.

[18]  N. Kadowaki,et al.  Natural Interferon α/β–Producing Cells Link Innate and Adaptive Immunity , 2000, The Journal of experimental medicine.

[19]  C A Smith,et al.  Identification and characterization of a new member of the TNF family that induces apoptosis. , 1995, Immunity.

[20]  O. Colamonici,et al.  The type-I interferon receptor. The long and short of it. , 1996, Cytokine & growth factor reviews.

[21]  L. Arthur,et al.  Microvesicles are a source of contaminating cellular proteins found in purified HIV-1 preparations. , 1997, Virology.

[22]  G. Trinchieri,et al.  Persistent Decreases in Blood Plasmacytoid Dendritic Cell Number and Function Despite Effective Highly Active Antiretroviral Therapy and Increased Blood Myeloid Dendritic Cells in HIV-Infected Individuals1 , 2002, The Journal of Immunology.

[23]  P. Reiss,et al.  High-dose interferon-alpha2a exerts potent activity against human immunodeficiency virus type 1 not associated with antitumor activity in subjects with Kaposi's sarcoma. , 1997, The Journal of infectious diseases.

[24]  J. Lifson,et al.  Partial Activation and Induction of Apoptosis in CD4+ and CD8+ T Lymphocytes by Conformationally Authentic Noninfectious Human Immunodeficiency Virus Type 1 , 2001, Journal of Virology.

[25]  Mamoru Ito,et al.  Critical Contribution of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (Trail) to Apoptosis of Human Cd4+T Cells in HIV-1–Infected Hu-Pbl-Nod-Scid Mice , 2001, The Journal of experimental medicine.

[26]  William J. Kaiser,et al.  Divergent Host Responses during Primary Simian Immunodeficiency Virus SIVsm Infection of Natural Sooty Mangabey and Nonnatural Rhesus Macaque Hosts , 2005, Journal of Virology.

[27]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[28]  F. Gheyas,et al.  Depletion of circulating natural type 1 interferon-producing cells in HIV-infected AIDS patients. , 2001, Blood.

[29]  J. Lifson,et al.  TNF-related apoptosis-inducing ligand (TRAIL) in HIV-1-infected patients and its in vitro production by antigen-presenting cells. , 2005, Blood.

[30]  P. Fitzgerald-Bocarsly,et al.  Interferon-alpha generation and immune reconstitution during antiretroviral therapy for human immunodeficiency virus infection. , 2001, AIDS.

[31]  J. Lifson,et al.  Human Immunodeficiency Virus Type 1 Activates Plasmacytoid Dendritic Cells and Concomitantly Induces the Bystander Maturation of Myeloid Dendritic Cells , 2004, Journal of Virology.

[32]  P. Fournel,et al.  Macrophages from cancer patients: analysis of TRAIL, TRAIL receptors, and colon tumor cell apoptosis. , 2003, Journal of the National Cancer Institute.

[33]  A. Badley,et al.  Induction of Cell Death in Human Immunodeficiency Virus-Infected Macrophages and Resting Memory CD4 T Cells by TRAIL/Apo2L , 2001, Journal of Virology.

[34]  C. Maliszewski,et al.  Plasmacytoid monocytes/T cells: a dendritic cell lineage? , 2001, Seminars in immunology.

[35]  M. Gardner,et al.  Human alpha- and beta-interferon but not gamma- suppress the in vitro replication of LAV, HTLV-III, and ARV-2. , 1986, Journal of interferon research.

[36]  J. Torres-Roca,et al.  Interleukin-1β Converting Enzyme–like Protease Involvement in Fas-induced and Activation-induced Peripheral Blood T Cell Apoptosis in HIV Infection. TNF-related Apoptosis-inducing Ligand Can Mediate Activation-induced T Cell Death in HIV Infection , 1997, The Journal of experimental medicine.

[37]  J. Darnell,et al.  Signalling: STATs: transcriptional control and biological impact , 2002, Nature Reviews Molecular Cell Biology.

[38]  K. Agrawal,et al.  Anti-HIV drugs: comparative toxicities in murine fetal liver and bone marrow erythroid progenitor cells. , 1989, Life sciences.

[39]  Jun Long Lim,et al.  Phosphorylated interferon‐alpha receptor 1 subunit (IFNaR1) acts as a docking site for the latent form of the 113 kDa STAT2 protein. , 1996, The EMBO journal.