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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 T cell receptor were the most significantly activated, despite the absence of canonical antigen dependent stimulation. The importance of this pathway was demonstrated by depletion of proteins and we show that HIV-1 Env mediated cell-cell contact, 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 new paradigm for antigen independent T cell signaling.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Jurkat Cell

DISEASE(S): Human Immunodeficiency Virus Infectious Disease

SUBMITTER: Clare Jolly

LAB HEAD: Clare Jolly

PROVIDER: PXD005658 | Pride | 2022-02-28

REPOSITORIES: Pride

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

Len Alice C L ACL Starling Shimona S Shivkumar Maitreyi M Jolly Clare C

Cell reports 20170101 4

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 downstr ...[more]

PMID: 28122231

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Project description:Wodarz2007 - HIV/CD4 T-cell interaction A deterministic model illustrating how CD4 T-cells can influence HIV infection. This model is described in the article: Infection dynamics in HIV-specific CD4 T cells: does a CD4 T cell boost benefit the host or the virus? Wodarz D, Hamer DH. Math Biosci 2007 Sep; 209(1): 14-29 Abstract: Recent experimental data have shown that HIV-specific CD4 T cells provide a very important target for HIV replication. We use mathematical models to explore the effect of specific CD4 T cell infection on the dynamics of virus spread and immune responses. Infected CD4 T cells can provide antigen for their own stimulation. We show that such autocatalytic cell division can significantly enhance virus spread, and can also provide an additional reservoir for virus persistence during anti-viral drug therapy. In addition, the initial number of HIV-specific CD4 T cells is an important determinant of acute infection dynamics. A high initial number of HIV-specific CD4 T cells can lead to a sudden and fast drop of the population of HIV-specific CD4 T cells which results quickly in their extinction. On the other hand, a low initial number of HIV-specific CD4 T cells can lead to a prolonged persistence of HIV-specific CD4 T cell help at higher levels. The model suggests that boosting the population of HIV-specific CD4 T cells can increase the amount of virus-induced immune impairment, lead to less efficient anti-viral effector responses, and thus speed up disease progression, especially if effector responses such as CTL have not been sufficiently boosted at the same time. This model is hosted on BioModels Database and identified by: BIOMD0000000663. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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