title: The regulated secretory pathway in CD4(+) T cells contributes to human immunodeficiency virus type-1 cell-to-cell spread at the virological synapse.
abstract: Direct cell-cell spread of Human Immunodeficiency Virus type-1 (HIV-1) at the virological synapse (VS) is an efficient mode of dissemination between CD4(+) T cells but the mechanisms by which HIV-1 proteins are directed towards intercellular contacts is unclear. We have used confocal microscopy and electron tomography coupled with functional virology and cell biology of primary CD4(+) T cells from normal individuals and patients with Chediak-Higashi Syndrome and report that the HIV-1 VS displays a regulated secretion phenotype that shares features with polarized secretion at the T cell immunological synapse (IS). Cell-cell contact at the VS re-orientates the microtubule organizing center (MTOC) and organelles within the HIV-1-infected T cell towards the engaged target T cell, concomitant with polarization of viral proteins. Directed secretion of proteins at the T cell IS requires specialized organelles termed secretory lysosomes (SL) and we show that the HIV-1 envelope glycoprotein (Env) localizes with CTLA-4 and FasL in SL-related compartments and at the VS. Finally, CD4(+) T cells that are disabled for regulated secretion are less able to support productive cell-to-cell HIV-1 spread. We propose that HIV-1 hijacks the regulated secretory pathway of CD4(+) T cells to enhance its dissemination.
authors: MRC Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London, United Kingdom. c.jolly@ucl.ac.uk
authors: Clare
authors: C
authors: Jolly
authors: Sonja
authors: S
authors: Welsch
authors: Stefanie
authors: S
authors: Michor
authors: Quentin J
authors: QJ
authors: Sattentau
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000502:physiology / Q000821:virology; D002478:Cells, Cultured; D002609:Chediak-Higashi Syndrome / Q000503:physiopathology / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008247:Lysosomes / Q000502:physiology; D018613:Microscopy, Confocal; D022101:Microtubule-Organizing Center / Q000502:physiology; D050765:Qa-SNARE Proteins / Q000502:physiology; D055571:Secretory Pathway; D013569:Synapses / Q000502:physiology*; D014764:Viral Proteins / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D050765:Qa-SNARE Proteins; D014764:Viral Proteins