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    Low-Level Ionizing Radiation Induces Selective Killing of HIV-1-Infected Cells with Reversal of Cytokine Induction Using mTOR Inhibitors

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    Author
    Pinto, Daniel O
    DeMarino, Catherine
    Vo, Thy T
    Cowen, Maria
    Kim, Yuriy
    Pleet, Michelle L
    Barclay, Robert A
    Noren Hooten, Nicole
    Evans, Michele K
    Heredia, Alonso
    Batrakova, Elena V
    Iordanskiy, Sergey
    Kashanchi, Fatah
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    Date
    2020-08-13
    Journal
    Viruses
    Publisher
    MDPI AG
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3390/v12080885
    Abstract
    HIV-1 infects 39.5 million people worldwide, and cART is effective in preventing viral spread by reducing HIV-1 plasma viral loads to undetectable levels. However, viral reservoirs persist by mechanisms, including the inhibition of autophagy by HIV-1 proteins (i.e., Nef and Tat). HIV-1 reservoirs can be targeted by the "shock and kill" strategy, which utilizes latency-reversing agents (LRAs) to activate latent proviruses and immunotarget the virus-producing cells. Yet, limitations include reduced LRA permeability across anatomical barriers and immune hyper-activation. Ionizing radiation (IR) induces effective viral activation across anatomical barriers. Like other LRAs, IR may cause inflammation and modulate the secretion of extracellular vesicles (EVs). We and others have shown that cells may secrete cytokines and viral proteins in EVs and, therefore, LRAs may contribute to inflammatory EVs. In the present study, we mitigated the effects of IR-induced inflammatory EVs (i.e., TNF-α), through the use of mTOR inhibitors (mTORi; Rapamycin and INK128). Further, mTORi were found to enhance the selective killing of HIV-1-infected myeloid and T-cell reservoirs at the exclusion of uninfected cells, potentially via inhibition of viral transcription/translation and induction of autophagy. Collectively, the proposed regimen using cART, IR, and mTORi presents a novel approach allowing for the targeting of viral reservoirs, prevention of immune hyper-activation, and selectively killing latently infected HIV-1 cells.
    Keyword
    HIV-1
    HIV-1 therapy
    Ionizing radiation
    autophagy
    cell death
    extracellular vesicles
    inflammation
    latency reversal
    mTOR inhibition
    shock and kill
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/13641
    ae974a485f413a2113503eed53cd6c53
    10.3390/v12080885
    Scopus Count
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    UMB Open Access Articles 2020

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