The Regulated Secretory Pathway in CD4+ T cells Contributes to Human Immunodeficiency Virus Type-1 Cell-to-Cell Spread at the Virological Synapse

PLoS Pathogens

Clare Jolly¹  Stefanie Michor²  Quentin J. Sattentau³  Sonja Welsch⁴ 

[1] MRC Centre for Medical Molecular Virology, Division of Infection and Immunity, University College London, London, United Kingdom;Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany;The Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom;Wellcome Trust Centre for Human Genetics, Division of Structural Biology, University of Oxford, Oxford, United Kingdom

关键词: HIV-1;    T cells;    Cell membranes;    Membrane proteins;    Cell staining;    Cellular structures;    organelles;    Secretion;    Viral replication;   

DOI  :  10.1371/journal.ppat.1002226

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY