title: HIV-1 Activates T Cell Signaling Independently of Antigen to Drive Viral Spread.
abstract: HIV-1 spreads between CD4 T cells most efficiently through virus-induced cell-cell contacts. To test whether this process potentiates viral spread by activating signaling pathways, we developed an approach to analyze the phosphoproteome in infected and uninfected mixed-population T cells using differential metabolic labeling and mass spectrometry. We discovered HIV-1-induced activation of signaling networks during viral spread encompassing over 200 cellular proteins. Strikingly, pathways downstream of the T cell receptor were the most significantly activated, despite the absence of canonical antigen-dependent stimulation. The importance of this pathway was demonstrated by the depletion of proteins, and we show that HIV-1 Env-mediated cell-cell contact, the T cell receptor, and the Src kinase Lck were essential for signaling-dependent enhancement of viral dissemination. This study demonstrates that manipulation of signaling at immune cell contacts by HIV-1 is essential for promoting virus replication and defines a paradigm for antigen-independent T cell signaling.
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, UK.
authors.forename: Alice C L
authors.initials: ACL
authors.lastname: Len
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, UK.
authors.forename: Shimona
authors.initials: S
authors.lastname: Starling
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, UK.
authors.forename: Maitreyi
authors.initials: M
authors.lastname: Shivkumar
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, UK. Electronic address: c.jolly@ucl.ac.uk.
authors.forename: Clare
authors.initials: C
authors.lastname: Jolly
mesh_terms: D000956:Antigens, Viral / Q000276:immunology*; D057809:HEK293 Cells; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D010748:Phosphopeptides / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D053586:Virus Internalization; D014779:Virus Replication; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000956:Antigens, Viral; D010748:Phosphopeptides; D011948:Receptors, Antigen, T-Cell; D019061:src-Family Kinases
keywords: HIV; T cell; TCR; phosphoproteomics; signaling; synapse