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Open AccessArticle

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

1
Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Manassas, VA 20110, USA
2
Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
3
Institute of Human Virology, University of Maryland School of Medicine, University of Maryland, Baltimore, MD 21201, USA
4
Department of Medicine, University of North Carolina HIV Cure Center; University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
5
Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
*
Author to whom correspondence should be addressed.
Viruses 2020, 12(8), 885; https://doi.org/10.3390/v12080885
Received: 17 July 2020 / Revised: 7 August 2020 / Accepted: 10 August 2020 / Published: 13 August 2020
(This article belongs to the Special Issue HIV-1 Latency: Regulation and Reversal)
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. View Full-Text
Keywords: HIV-1; autophagy; extracellular vesicles; latency reversal; Ionizing radiation; cell death; shock and kill; mTOR inhibition; HIV-1 therapy; inflammation HIV-1; autophagy; extracellular vesicles; latency reversal; Ionizing radiation; cell death; shock and kill; mTOR inhibition; HIV-1 therapy; inflammation
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Pinto, D.O.; DeMarino, C.; Vo, T.T.; Cowen, M.; Kim, Y.; Pleet, M.L.; Barclay, R.A.; Noren Hooten, N.; Evans, M.K.; Heredia, A.; Batrakova, E.V.; Iordanskiy, S.; Kashanchi, F. Low-Level Ionizing Radiation Induces Selective Killing of HIV-1-Infected Cells with Reversal of Cytokine Induction Using mTOR Inhibitors. Viruses 2020, 12, 885.

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