title: HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-Golgi network-associated Lck signaling.
abstract: The Nef protein of HIV-1 facilitates viral replication and disease progression in vivo. Nef disturbs the organization of immunological synapses between infected CD4(+) T lymphocytes and antigen-presenting B-lymphocytes to interfere with TCR proximal signaling. Paradoxically, Nef enhances distal TCR signaling in infected CD4(+) T lymphocytes, an effect thought to be involved in its role in AIDS pathogenesis. Using quantitative confocal microscopy and cell fractionation of Nef-expressing cells and HIV-1-infected primary human T lymphocytes, we found that Nef induces intracellular compartmentalization of TCR signaling to adjust TCR responses to antigenic stimulation. Nef reroutes kinase-active pools of the TCR signaling master switch Lck away from the plasma membrane (PM) to the trans-Golgi network (TGN), thereby preventing the recruitment of active Lck to the immunological synapse after TCR engagement and limiting signal initiation at the PM. Instead, Nef triggers Lck-dependent activation of TGN-associated Ras-Erk signaling to promote the production of the T lymphocyte survival factor IL-2 and to enhance virus spread. Overexpression of the Lck PM transporter Unc119 restores Nef-induced subversions of Lck trafficking and TCR signaling. Nef therefore hijacks Lck sorting to selectively activate TGN-associated arms of compartmentalized TCR signaling. By tailoring T-lymphocyte responses to antigenic stimulation, Nef optimizes the environment for HIV-1 replication.
authors: Department of Infectious Diseases, Virology, University Hospital Heidelberg, Germany.
authors: Xiaoyu
authors: X
authors: Pan
authors: Jochen M
authors: JM
authors: Rudolph
authors: Libin
authors: L
authors: Abraham
authors: Anja
authors: A
authors: Habermann
authors: Claudia
authors: C
authors: Haller
authors: Jacomine
authors: J
authors: Krijnse-Locker
authors: Oliver T
authors: OT
authors: Fackler
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002450:Cell Communication; D004797:Enzyme-Linked Immunosorbent Assay; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D054992:Immunological Synapses / Q000502:physiology*; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014779:Virus Replication / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology / Q000378:metabolism*; D021601:trans-Golgi Network / Q000276:immunology* / Q000378:metabolism / Q000821:virology
chemical_list: D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D054311:nef Gene Products, Human Immunodeficiency Virus; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)