Arsenic Trioxide Impacts Viral Latency and Delays Viral Rebound after Termination of ART in Chronically SIV‐Infected Macaques

Yang, Qing; Feng, Fengling; Li, Pingchao; Pan, Enxiang; Wu, Chunxiu; He, Yizi; Zhang, Fan; Zhao, Jin; Li, Ruiting; Feng, Liqiang; Hu, Fengyu; Li, Linghua; Zou, Huachun; Cai, Weiping; Lehner, Thomas; Sun, Caijun; Chen, Ling

doi:10.1002/advs.201900319

Cited by 29 publications

(34 citation statements)

References 44 publications

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“… Farsalinos et al, 2020 , Heo et al, 2017 , Li et al, 2017 , Li et al, 2020 , Penta et al, 2015 , Singhal, 2020 , Tinkov et al, 2018 , Tsatsakis et al, 2020 , Wu et al, 2020 , Xu et al, 2017 , Yang et al, 2019 Xu et al, 2017, Li et al, 2020, .…”

Section: Uncited Referencementioning

confidence: 99%

Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases

Skalny

Lima

Tao

et al. 2020

Food and Chemical Toxicology

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Multiple medical, lifestyle, and environmental conditions, including smoking and particulate pollution, have been considered as risk factors for CO rona VI rus D isease 2019 (COVID-19) susceptibility and severity. Taking into account the high level of toxic metals in both particulate matter (PM2.5) and tobacco smoke, the objective of this review is to discuss recent data on the role of heavy metal exposure in development of respiratory dysfunction, immunotoxicity, and severity of viral diseases in epidemiological and experimental studies, as to demonstrate the potential crossroads between heavy metal exposure and COVID-19 severity risk. The existing data demonstrate that As, Cd, Hg, and Pb exposure is associated with respiratory dysfunction and respiratory diseases (COPD, bronchitis). These observations corroborate laboratory findings on the role of heavy metal exposure in impaired mucociliary clearance, reduced barrier function, airway inflammation, oxidative stress, and apoptosis. The association between heavy metal exposure and severity of viral diseases, including influenza and respiratory syncytial virus has been also demonstrated. The latter may be considered a consequence of adverse effects of metal exposure on adaptive immunity. Therefore, reduction of toxic metal exposure may be considered as a potential tool for reducing susceptibility and severity of viral diseases affecting the respiratory system, including COVID-19.

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Section: Uncited Referencementioning

confidence: 99%

Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases

Skalny

Lima

Tao

et al. 2020

Food and Chemical Toxicology

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“…In the case of HIV‐1, PML was shown to play an important role in the epigenetic control of viral transcription, contributing mainly to latency maintenance through its interaction with histone methyltransferase G9a (Lusic et al , ). Moreover, PML is the main therapeutic target of arsenic trioxide (ATO), a drug approved for the treatment of acute promyelocytic leukemia and shown to have anti‐HIV‐1 latency potential in vitro (Lusic et al , ) and in vivo (Yang et al , ). ATO can induce oxidative stress, and it has been recently proposed that the oxidation process per se can modulate the biogenesis and turnover of PML NBs through post‐translational modifications (Sahin et al , ,b; Niwa‐Kawakita et al , ).…”

Section: Introductionmentioning

confidence: 99%

Alterations of redox and iron metabolism accompany the development of HIV latency

et al. 2020

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HIV-1 persists in a latent form during antiretroviral therapy, mainly in CD4 + T cells, thus hampering efforts for a cure. HIV-1 infection is accompanied by metabolic alterations, such as oxidative stress, but the effect of cellular antioxidant responses on viral replication and latency is unknown. Here, we show that cells survive retroviral replication, both in vitro and in vivo in SIVmacinfected macaques, by upregulating antioxidant pathways and the intertwined iron import pathway. These changes are associated with remodeling of promyelocytic leukemia protein nuclear bodies (PML NBs), an important constituent of nuclear architecture and a marker of HIV-1 latency. We found that PML NBs are hyper-SUMOylated and that PML protein is degraded via the ubiquitinproteasome pathway in productively infected cells, before latency establishment and after reactivation. Conversely, normal numbers of PML NBs were restored upon transition to latency or by decreasing oxidative stress or iron content. Our results highlight antioxidant and iron import pathways as determinants of HIV-1 latency and support their pharmacologic inhibition as tools to regulate PML stability and impair latency establishment.

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“…A similar effect was observed in macaques treated with another prooxidant compound and Trx pathway inhibitor, i.e. arsenic trioxide (Yang et al, 2019). One characteristic of these strategies was not only the elimination of latently infected cells in vivo but also the enhancement of anti-HIV-1 cell mediated immunity (Shytaj et al, 2015).…”

Section: Discussionmentioning

confidence: 58%

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

Shytaj

Procopio

Tarek

et al. 2020

Preprint

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HIV-1 infects lymphoid and myeloid cells, which can harbor a latent proviral reservoir responsible for maintaining lifelong infection. Glycolytic metabolism has been identified as a determinant of susceptibility to HIV-1 infection, but its role in the development and maintenance of HIV-1 latency has not been elucidated. By combining transcriptomic, proteomic and metabolomic analysis, we here show that transition to latent HIV-1 infection downregulates glycolysis, while viral reactivation by conventional stimuli reverts this effect. Decreased glycolytic output in latently infected cells is associated with downregulation of NAD+/NADH. Consequently, infected cells rely on the parallel pentose phosphate pathway and its main product, the antioxidant NADPH, fueling antioxidant pathways maintaining HIV-1 latency. Of note, blocking NADPH downstream effectors, thioredoxin and glutathione, favors HIV-1 reactivation from latency in lymphoid and myeloid cellular models. This provides a “shock and kill effect” decreasing proviral DNA in cells from people-living-with-HIV/AIDS. Overall, our data show that downmodulation of glycolysis is a metabolic signature of HIV-1 latency that can be exploited to target latently infected cells with eradication strategies.

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Arsenic Trioxide Impacts Viral Latency and Delays Viral Rebound after Termination of ART in Chronically SIV‐Infected Macaques

Cited by 29 publications

References 44 publications

Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases

Toxic metal exposure as a possible risk factor for COVID-19 and other respiratory infectious diseases

Alterations of redox and iron metabolism accompany the development of HIV latency

Glycolysis downregulation is a hallmark of HIV-1 latency and sensitizes infected cells to oxidative stress

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