Low-Level Ionizing Radiation Induces Selective Killing of HIV-1-Infected Cells with Reversal of Cytokine Induction Using mTOR Inhibitors
Author
Pinto, Daniel ODeMarino, 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
Date
2020-08-13Journal
VirusesPublisher
MDPI AGType
Article
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Show full item recordAbstract
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-1HIV-1 therapy
Ionizing radiation
autophagy
cell death
extracellular vesicles
inflammation
latency reversal
mTOR inhibition
shock and kill
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http://hdl.handle.net/10713/13641ae974a485f413a2113503eed53cd6c53
10.3390/v12080885
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