HIV-1 Activates T Cell Signaling Independently of Antigen to Drive Viral Spread

• Published in: Cell reports (Cambridge) 2017-01, Vol.18 (4), p.1062-1074
• Main Authors: Len, Alice C.L., Starling, Shimona, Shivkumar, Maitreyi, Jolly, Clare
• Format: Article
• Language: English
• Subjects: Antigens, Viral - immunology; HEK293 Cells; HIV; HIV-1 - physiology; Humans; Jurkat Cells; Lymphocyte Activation; Mass Spectrometry; Microscopy, Fluorescence; Phosphopeptides - analysis; phosphoproteomics; Receptors, Antigen, T-Cell - metabolism; Resource; Signal Transduction; signaling; src-Family Kinases - metabolism; synapse; T cell; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; T-Lymphocytes - virology; TCR; Virus Internalization; Virus Replication
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.12.057

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. [Display omitted] •Unbiased global analysis of T cell signaling changes during HIV-1 cell-cell spread•Experimental system to map dynamic signaling changes in mixed cell populations over time•More than 200 host cell proteins are modified as HIV-1 disseminates between T cells•HIV-1 activates antigen-independent TCR signaling to drive viral spread HIV-1 rapidly spreads between T cells. Len et al. have developed an approach to interrogate real-time signaling changes in infected and uninfected cells during viral dissemination. They report that HIV-1-induced cell-cell contact activates antigen-independent T cell signaling that is necessary for HIV-1 to spread efficiently between cells.