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.

中文翻译：

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氧化还原和铁代谢的改变伴随着艾滋病毒潜伏期的发展。

HIV-1在抗逆转录病毒治疗期间以潜伏形式持续存在，主要存在于CD4+ T细胞中，从而阻碍了治愈的努力。HIV-1感染伴随着氧化应激等代谢改变，但细胞抗氧化反应对病毒复制和潜伏期的影响尚不清楚。在这里，我们发现，在 SIVmac 感染的猕猴体内和体外，细胞通过上调抗氧化途径和相互交织的铁输入途径，在逆转录病毒复制中存活下来。这些变化与早幼粒细胞白血病蛋白核体 (PML NB) 的重塑有关，PML NB 是核结构的重要组成部分，也是 HIV-1 潜伏期的标志。我们发现，在潜伏期建立之前和重新激活之后，PML NB 被过度 SUMO 化，并且 PML 蛋白在有效感染细胞中通过泛素蛋白酶体途径降解。相反，PML NB 的正常数量在过渡到潜伏期或通过减少氧化应激或铁含量而恢复。我们的结果强调抗氧化剂和铁输入途径是 HIV-1 潜伏期的决定因素，并支持它们的药理学抑制作为调节 PML 稳定性和损害潜伏期建立的工具。