Abstract
Human immunodeficiency virus 1 (HIV-1) is a life-threatening pathogen that still lacks a curative therapy or vaccine. Despite the reduction in AIDS-related deaths achieved by current antiretroviral therapies, drawbacks including drug resistance and the failure to eradicate infection highlight the need to identify new pathways to target the infection. Circadian rhythms are endogenous 24-h oscillations which regulate physiological processes including immune responses to infection, and there is an emerging role for the circadian components in regulating viral replication. The molecular clock consists of transcriptional/translational feedback loops that generate rhythms. In mammals, BMAL1 and CLOCK activate rhythmic transcription of genes including the nuclear receptor REV-ERBα, which represses BMAL1 and plays an essential role in sustaining a functional clock. We investigated whether REV-ERB activity regulates HIV-1 replication and found REV-ERB agonists inhibited HIV-1 promoter activity in cell lines, primary human CD4 T cells and macrophages, whilst antagonism or genetic disruption of REV-ERB increased promoter activity. The REV-ERB agonist SR9009 inhibited promoter activity of diverse HIV-subtypes and HIV-1 replication in primary T cells. This study shows a role for REV-ERB synthetic agonists to inhibit HIV-1 LTR promoter activity and viral replication, supporting a role for circadian clock components in regulating HIV-1 replication.
Highlights
All life forms have evolved under a rhythmically changing light/dark cycle due to the Earth’s rotation
Chang et al recently reported that BMAL1 positively regulates the Human immunodeficiency virus 1 (HIV-1) long terminal repeat (LTR) activity through E-box motifs t herein[20] (Fig. 1)
We show that REV-ERB synthetic ligands inhibit HIV-1 LTR promoter activity and viral replication, supporting a role for circadian clock transcription factors in regulating HIV-1 replication
Summary
All life forms have evolved under a rhythmically changing light/dark cycle due to the Earth’s rotation. The HIV-1 long terminal repeat (LTR) promoter encodes regulatory elements that bind viral or cellular trans-activating factors that regulate its a ctivity[19], demonstrating the innate dependency of the virus on host cell components to replicate. Chang et al recently reported that BMAL1 positively regulates the HIV-1 LTR activity through E-box motifs t [20] (Fig. 1).
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