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.
Highlights
HIV-1 persists in a latent form during antiretroviral therapy, mainly in CD4+ T cells, hampering efforts for a cure
We further show that oxidative stress and iron import during productive HIV-1 infection mediate depletion of Promyelocytic leukemia nuclear bodies (PML NBs) through SUMO modification and ubiquitin-mediated proteasomal degradation
To study the expression of antioxidant genes and proteins during the different stages of HIV-1 infection, we used a primary CD4+ T-cell model similar to those previously adopted by several groups (Bosque & Planelles, 2009; Lusic et al, 2013; Martins et al, 2016)
Summary
HIV-1 persists in a latent form during antiretroviral therapy, mainly in CD4+ T cells, hampering efforts for a cure. 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 hyperSUMOylated and that PML protein is degraded via the ubiquitin– proteasome pathway in productively infected cells, before latency establishment and after reactivation. Identifying the antioxidant species and pathways which regulate the response to HIV-1-induced oxidative stress is required to define and characterize their role in the transition from productive to latent infection. The pathway here reconstructed highlights metabolic correlates of latency and shows that Nrf2-signaling, iron import, and PML are intertwined, providing potential druggable targets for combined therapeutic applications
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