Abstract
SummaryHIV-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.
Highlights
Many viruses exploit direct cell-cell infection to replicate most efficiently
Cell-cell spread is the predominant mode of HIV-1 replication (Hu€bner et al, 2009; Jolly et al, 2007b; Martin et al, 2010; Sourisseau et al, 2007) that leads to T cell depletion and the development of AIDS
By simultaneously mapping real-time phosphorylation changes in HIV-1-infected and HIV-1-uninfected CD4 T cells with kinetic resolution, we identified the host cell pathways and cellular factors modified during HIV-1 dissemination
Summary
HIV-1 is no exception and has evolved to take advantage of the frequent interactions between immune cells in lymphoid tissue to disseminate at sites of T cell-T cell contact (Jolly et al, 2004; Murooka et al, 2012; Sewald et al, 2012). Cell-cell spread is the predominant mode of HIV-1 replication (Hu€bner et al, 2009; Jolly et al, 2007b; Martin et al, 2010; Sourisseau et al, 2007) that leads to T cell depletion and the development of AIDS. Cell-cell spread of HIV-1 occurs across virus-induced T cell-T cell contacts (virological synapses [VSs]; Jolly et al, 2004) and is a dynamic, calcium-dependent process that appears highly regulated (Martin et al, 2010; Groppelli et al, 2015), culminating in polarized viral egress and rapid infection of neighboring cells. Whether cell-cell spread induces signals that potentiate viral replication has been little considered but has major implications for therapeutic and eradication strategies
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