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HIV-1 promoter activation following an oxidative stress mediated by singlet oxygen
S Legrand-Poels1, M Hoebeke, D Vaira
1Laboratory of Virology, Institute of Pathology, University of Liège, Belgium.
Abstract:
Various biological processes, such as photosensitization or inflammatory reactions, can generate singlet oxygen (1O2) as one of the major oxidative species. Because this oxidant can be generated either extracellularly or intracellularly, it can cause severe damage to various biological macromolecules, even to those deeply embedded inside the cells such as DNA. Sublethal biological modifications induced by different DNA-damaging agents can promote various cellular responses initiated by the activation of various cellular genes and certain heterologous viruses. Since 1O2 fulfils essential prerequisites for a genotoxic substance, we have examined the effects of an oxidative stress, mediated by this species, on cells harbouring a heterologous promoter-leader sequence derived from the human immunodeficiency virus type 1 (HIV-1). Our results demonstrate that HIV-1 long terminal repeat (LTR), integrated into the cellular DNA of epithelial cells, can be transactivated following an oxidative stress mediated by 1O2. In addition, using HIV-1 latently infected promonocytes or lymphocytes, it can be shown that virus reactivation can be induced through a sublethal dose of 1O2 generated intracellularly. An extracellular generation of 1O2 can promote a substantial lethal effect without HIV-1 reactivation. These data may be relevant to the understanding of the events converting a latent infection into a productive one and to the appearance of the acquired immune deficiency syndrome.
Insights
Singlet oxygen (1O2) can activate the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) and reactivate latent HIV-1 infections. This oxidative stress can trigger viral replication, potentially impacting AIDS progression.
Area of Science:
- Cellular biology
- Molecular biology
- Virology
Background:
- Singlet oxygen (1O2) is a reactive oxygen species generated during various biological processes.
- 1O2 can cause significant damage to cellular macromolecules, including DNA, and trigger cellular responses.
- Oxidative stress is implicated in various diseases and cellular dysfunctions.
Purpose of the Study:
- To investigate the genotoxic effects of singlet oxygen (1O2) on cellular systems.
- To determine if 1O2 can activate the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR).
- To examine the role of intracellularly and extracellularly generated 1O2 in HIV-1 reactivation.
Main Methods:
- Exposure of epithelial cells with integrated HIV-1 LTR to 1O2.
- Treatment of latently HIV-1 infected promonocytes and lymphocytes with intracellularly generated 1O2.
- Assessment of HIV-1 LTR transactivation and viral reactivation.
Main Results:
- Oxidative stress mediated by 1O2 transactivated the HIV-1 LTR in epithelial cells.
- Intracellular 1O2 generation induced reactivation of latent HIV-1 in infected immune cells.
- Extracellular 1O2 caused cell death but did not induce HIV-1 reactivation.
Conclusions:
- Singlet oxygen acts as a genotoxic agent capable of activating HIV-1 gene expression.
- Intracellular 1O2 can trigger the reactivation of latent HIV-1 infections.
- These findings offer insights into the mechanisms of HIV-1 latency conversion and AIDS pathogenesis.