Shytaj, Iart Luca ORCID: 0000-0002-9980-1275, Lucic, Bojana ORCID: 0000-0001-5300-2489, Forcato, Mattia, Penzo, Carlotta, Billingsley, James, Laketa, Vibor, Bosinger, Steven, Stanic, Mia, Gregoretti, Francesco ORCID: 0000-0003-3822-1215, Antonelli, Laura ORCID: 0000-0002-4031-099X, Oliva, Gennaro, Frese, Christian K., Trifunovic, Aleksandra, Galy, Bruno, Eibl, Clarissa, Silvestri, Guido, Bicciato, Silvio ORCID: 0000-0002-1944-7078, Savarino, Andrea ORCID: 0000-0003-0983-3693 and Lusic, Marina (2020). Alterations of redox and iron metabolism accompany the development of HIV latency. Embo J., 39 (9). HOBOKEN: WILEY. ISSN 1460-2075

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Abstract

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 SIVmac-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 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 ubiquitin-proteasome 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Shytaj, Iart LucaUNSPECIFIEDorcid.org/0000-0002-9980-1275UNSPECIFIED
Lucic, BojanaUNSPECIFIEDorcid.org/0000-0001-5300-2489UNSPECIFIED
Forcato, MattiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Penzo, CarlottaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Billingsley, JamesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laketa, ViborUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bosinger, StevenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stanic, MiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gregoretti, FrancescoUNSPECIFIEDorcid.org/0000-0003-3822-1215UNSPECIFIED
Antonelli, LauraUNSPECIFIEDorcid.org/0000-0002-4031-099XUNSPECIFIED
Oliva, GennaroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frese, Christian K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trifunovic, AleksandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galy, BrunoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eibl, ClarissaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Silvestri, GuidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bicciato, SilvioUNSPECIFIEDorcid.org/0000-0002-1944-7078UNSPECIFIED
Savarino, AndreaUNSPECIFIEDorcid.org/0000-0003-0983-3693UNSPECIFIED
Lusic, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-341206
DOI: 10.15252/embj.2019102209
Journal or Publication Title: Embo J.
Volume: 39
Number: 9
Date: 2020
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1460-2075
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PML NUCLEAR-BODIES; CD4(+) T-CELLS; OXIDATIVE STRESS; INFECTION; CANCER; COMMUNICATION; REACTIVATION; MODULATION; MECHANISMS; INDUCTIONMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34120

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