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Alterations of redox and iron metabolism accompany the development of HIV latency
Author(s) -
Shytaj Iart Luca,
Lucic Bojana,
Forcato Mattia,
Penzo Carlotta,
Billingsley James,
Laketa Vibor,
Bosinger Steven,
Stanic Mia,
Gregoretti Francesco,
Antonelli Laura,
Oliva Gennaro,
Frese Christian K,
Trifunovic Aleksandra,
Galy Bruno,
Eibl Clarissa,
Silvestri Guido,
Bicciato Silvio,
Savarino Andrea,
Lusic Marina
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019102209
Subject(s) - biology , oxidative stress , latency (audio) , proteasome , microbiology and biotechnology , ubiquitin , viral replication , virus latency , antioxidant , immunology , biochemistry , virus , gene , engineering , electrical engineering
HIV ‐1 persists in a latent form during antiretroviral therapy, mainly in CD 4 + 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 SIV mac‐infected macaques, by upregulating antioxidant pathways and the intertwined iron import pathway. These changes are associated with remodeling of promyelocytic leukemia protein nuclear bodies ( PML NB s), an important constituent of nuclear architecture and a marker of HIV ‐1 latency. We found that PML NB s are hyper‐ SUMO ylated and that PML protein is degraded via the ubiquitin–proteasome pathway in productively infected cells, before latency establishment and after reactivation. Conversely, normal numbers of PML NB s 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.