Pharmacological activation of the circadian component REV-ERB inhibits HIV-1 replication.
Antiviral Agents
/ pharmacology
CD4-Positive T-Lymphocytes
/ cytology
Cell Line
Circadian Clocks
/ drug effects
HIV Long Terminal Repeat
/ drug effects
HIV-1
/ drug effects
Humans
Jurkat Cells
Macrophages
/ cytology
Promoter Regions, Genetic
/ drug effects
Pyrrolidines
/ pharmacology
Receptors, Thyroid Hormone
/ metabolism
Thiophenes
/ pharmacology
Virus Replication
/ drug effects
rev Gene Products, Human Immunodeficiency Virus
/ metabolism
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
06 08 2020
06 08 2020
Historique:
received:
09
04
2020
accepted:
07
07
2020
entrez:
9
8
2020
pubmed:
9
8
2020
medline:
16
12
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32764708
doi: 10.1038/s41598-020-70170-3
pii: 10.1038/s41598-020-70170-3
pmc: PMC7413328
doi:
Substances chimiques
Antiviral Agents
0
Pyrrolidines
0
Receptors, Thyroid Hormone
0
SR9009
0
Thiophenes
0
rev Gene Products, Human Immunodeficiency Virus
0
rev protein, Human Immunodeficiency Virus-1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
13271Subventions
Organisme : Medical Research Council
ID : G0400802
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0801976
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R022011/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : IA 200838/Z/16/Z
Pays : United Kingdom
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