HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-golgi network-associated Lck signaling
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 si...
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| Hauptverfasser: | , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2012
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| In: |
Blood
Year: 2011, Jahrgang: 119, Heft: 3, Pages: 786-797 |
| ISSN: | 1528-0020 |
| DOI: | 10.1182/blood-2011-08-373209 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1182/blood-2011-08-373209 Verlag, kostenfrei, Volltext: http://www.bloodjournal.org/content/119/3/786 
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| Verfasserangaben: | Xiaoyu Pan, Jochen M. Rudolph, Libin Abraham, Anja Habermann, Claudia Haller, Jacomine Krijnse-Locker, and Oliver T. Fackler |
| Zusammenfassung: | 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. |
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| Beschreibung: | Published online: November 28, 2011 Gesehen am 04.06.2018 |
| Beschreibung: | Online Resource |
| ISSN: | 1528-0020 |
| DOI: | 10.1182/blood-2011-08-373209 |