Browsing by Author "Jolly, Clare"

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    HIV-1 Activates T Cell Signaling Independently of Antigen to Drive Viral Spread
    (Elsevier, 2017-01-24) Starling, Shimona; Shivkumar, Maitreyi; Jolly, Clare; Len, Alice C.L.
    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.
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    HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells.
    (Elsevier, 2022-04-12) Reushl, Ann-Kathrin; Mesner, Dejan; Shivkumar, Maitreyi; Whelan, Matthew V X; Pallett, Laura J; Guerra-Assunção, José Afonso; Madansein, Rajhmun; Dullabh, Kaylesh J; Sigal, Alex; Thornhill, John P; Herrera, Carolina; Fidler, Sarah; Noursadeghi, Mahdad; Maini, Mala K; Jolly, Clare
    HIV-1 replicates in CD4+ T cells, leading to AIDS. Determining how HIV-1 shapes its niche to create a permissive environment is central to informing efforts to limit pathogenesis, disturb reservoirs, and achieve a cure. A key roadblock in understanding HIV-T cell interactions is the requirement to activate T cells in vitro to make them permissive to infection. This dramatically alters T cell biology and virus-host interactions. Here we show that HIV-1 cell-to-cell spread permits efficient, productive infection of resting memory T cells without prior activation. Strikingly, we find that HIV-1 infection primes resting T cells to gain characteristics of tissue-resident memory T cells (TRM), including upregulating key surface markers and the transcription factor Blimp-1 and inducing a transcriptional program overlapping the core TRM transcriptional signature. This reprogramming is driven by Vpr and requires Vpr packaging into virions and manipulation of STAT5. Thus, HIV-1 reprograms resting T cells, with implications for viral replication and persistence.