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Molecular components of the circadian clock regulate HIV-1 replication.

ABSTRACT: Human immunodeficiency virus 1 (HIV-1) causes major health burdens worldwide and still lacks curative therapies and vaccines. Circadian rhythms are endogenous daily oscillations that coordinate an organism's response to its environment and invading pathogens. Peripheral viral loads of HIV-1 infected patients show diurnal variation; however, the underlying mechanisms remain unknown. Here, we demonstrate a role for the cell-intrinsic clock to regulate rhythmic HIV-1 replication in circadian-synchronized systems. Silencing the circadian activator Bmal1 abolishes this phenotype, and we observe BMAL1 binding to the HIV-1 promoter. Importantly, we show differential binding of the nuclear receptors REV-ERB and ROR to the HIV-long terminal repeat at different circadian times, demonstrating a dynamic interplay in time-of-day regulation of HIV-1 transcription. Bioinformatic analysis shows circadian regulation of host factors that control HIV-1 replication, providing an additional mechanism for rhythmic viral replication. This study increases our understanding of the circadian regulation of HIV-1, which can ultimately inform new therapies.

SUBMITTER: Borrmann H

PROVIDER: S-EPMC10391662 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Molecular components of the circadian clock regulate HIV-1 replication.

Borrmann Helene H Ulkar Görkem G Kliszczak Anna E AE Ismed Dini D Schilling Mirjam M Magri Andrea A Harris James M JM Balfe Peter P Vasudevan Sridhar S Borrow Persephone P Zhuang Xiaodong X McKeating Jane A JA

iScience 20230529 7

Human immunodeficiency virus 1 (HIV-1) causes major health burdens worldwide and still lacks curative therapies and vaccines. Circadian rhythms are endogenous daily oscillations that coordinate an organism's response to its environment and invading pathogens. Peripheral viral loads of HIV-1 infected patients show diurnal variation; however, the underlying mechanisms remain unknown. Here, we demonstrate a role for the cell-intrinsic clock to regulate rhythmic HIV-1 replication in circadian-synchr ...[more]

PMID: 37534138

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Project description:In mammals, most cells in the brain and peripheral tissues generate circadian (∼24 h) rhythms autonomously. These self-sustained rhythms are coordinated and entrained by a master circadian clock in the suprachiasmatic nucleus (SCN). Within the SCN, the individual rhythms of each neuron are synchronized through intercellular signaling. One important feature of SCN is that the synchronized period is close to the population mean of cells' intrinsic periods. In this way, the synchronized period of the SCN stays close to the periods of cells in peripheral tissues. This is important because the SCN must entrain cells throughout the body. However, the mechanism that drives the period of the coupled SCN cells to the population mean is not known. We use mathematical modeling and analysis to show that the mechanism of transcription repression in the intracellular feedback loop plays a pivotal role in regulating the coupled period. Specifically, we use phase response curve analysis to show that the coupled period within the SCN stays near the population mean if transcriptional repression occurs via protein sequestration. In contrast, the coupled period is far from the mean if repression occurs through highly nonlinear Hill-type regulation (e.g., oligomer- or phosphorylation-based repression), as widely assumed in previous mathematical models. Furthermore, we find that the timescale of intercellular coupling needs to be fast compared to that of intracellular feedback to maintain the mean period. These findings reveal the important relationship between the intracellular transcriptional feedback loop and intercellular coupling. This relationship explains why transcriptional repression appears to occur via protein sequestration in multicellular organisms, mammals, and Drosophila, in contrast with the phosphorylation-based repression in unicellular organisms and syncytia. That is, transition to protein sequestration is essential for synchronizing multiple cells with a period close to the population mean (∼24 h).

Dataset Information

Molecular components of the circadian clock regulate HIV-1 replication.

Publications

Molecular components of the circadian clock regulate HIV-1 replication.

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