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Extracellular Vesicles in Viral Spread and Antiviral Response
Article

Extracellular Vesicle Activation of Latent HIV-1 Is Driven by EV-Associated c-Src and Cellular SRC-1 via the PI3K/AKT/mTOR Pathway

Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA
*
Author to whom correspondence should be addressed.
Those authors contributed equally to this work.
Received: 23 April 2020 / Revised: 8 June 2020 / Accepted: 17 June 2020 / Published: 19 June 2020
(This article belongs to the Special Issue Viruses and Extracellular Vesicles)
HIV-1 is a global health crisis that has infected more than 37 million people. Latent reservoirs throughout the body are a major hurdle when it comes to eradicating the virus. In our previous study, we found that exosomes, a type of extracellular vesicle (EV), from uninfected cells activate the transcription of HIV-1 in latent infected cells, regardless of combination antiretroviral therapy (cART). In this study, we investigated the specific mechanism behind the EV activation of latent HIV-1. We found that phosphorylated c-Src is present in EVs of various cell lines and has the ability to activate downstream proteins such as EGFR, initiating a signal cascade. EGFR is then able to activate the PI3K/AKT/mTOR pathway, resulting in the activation of STAT3 and SRC-1, culminating in the reversal of HIV-1 latency. This was verified by examining levels of HIV-1 TAR, genomic RNA and HIV-1 Gag p24 protein in cell lines and primary cells. We found that EVs containing c-Src rescued HIV-1 despite the presence of inhibitors, validating the importance of EV-associated c-Src in latent HIV-1 activation. Lastly, we discovered an increased recruitment of p300 and NF-κB in the nucleus of EV-treated infected cells. Collectively, our data suggest that EV-associated c-Src is able to activate latent HIV-1 via the PI3K/AKT/mTOR pathway and SRC-1/p300-driven chromatin remodeling. These findings could aid in designing new strategies to prevent the reactivation of latent HIV-1 in patients under cART. View Full-Text
Keywords: HIV-1; extracellular vesicle; c-Src; PI3/AKT/mTOR pathway; SRC-1 HIV-1; extracellular vesicle; c-Src; PI3/AKT/mTOR pathway; SRC-1
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MDPI and ACS Style

Barclay, R.A.; Mensah, G.A.; Cowen, M.; DeMarino, C.; Kim, Y.; Pinto, D.O.; Erickson, J.; Kashanchi, F. Extracellular Vesicle Activation of Latent HIV-1 Is Driven by EV-Associated c-Src and Cellular SRC-1 via the PI3K/AKT/mTOR Pathway. Viruses 2020, 12, 665. https://0-doi-org.brum.beds.ac.uk/10.3390/v12060665

AMA Style

Barclay RA, Mensah GA, Cowen M, DeMarino C, Kim Y, Pinto DO, Erickson J, Kashanchi F. Extracellular Vesicle Activation of Latent HIV-1 Is Driven by EV-Associated c-Src and Cellular SRC-1 via the PI3K/AKT/mTOR Pathway. Viruses. 2020; 12(6):665. https://0-doi-org.brum.beds.ac.uk/10.3390/v12060665

Chicago/Turabian Style

Barclay, Robert A., Gifty A. Mensah, Maria Cowen, Catherine DeMarino, Yuriy Kim, Daniel O. Pinto, James Erickson, and Fatah Kashanchi. 2020. "Extracellular Vesicle Activation of Latent HIV-1 Is Driven by EV-Associated c-Src and Cellular SRC-1 via the PI3K/AKT/mTOR Pathway" Viruses 12, no. 6: 665. https://0-doi-org.brum.beds.ac.uk/10.3390/v12060665

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