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PADI4-mediated citrullination of histone H3 stimulates HIV-1 transcription
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PADI4-mediated citrullination of histone H3 stimulates HIV-1 transcription
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Journal Article
PADI4-mediated citrullination of histone H3 stimulates HIV-1 transcription
2025
Overview
HIV-1 infection establishes a reservoir of long-lived cells with integrated proviral DNA that can persist despite antiretroviral therapy (ART). Certain reservoir cells can be reactivated to reinitiate infection. The mechanisms governing proviral latency and transcriptional regulation of the provirus are complex. Here, we identify a role for histone H3 citrullination, a post-translational modification catalyzed by protein-arginine deiminase type-4 (PADI4), in HIV-1 transcription and latency. PADI4 inhibition by the small molecule inhibitor GSK484 reduces HIV-1 transcription after T cell activation in ex vivo cultures of CD4
+
T cells from people living with HIV-1 in a cross-sectional study. The effect is more pronounced in individuals with active viremia compared to individuals under effective ART. Cell models of HIV-1 latency show that citrullination of histone H3 occurs at the HIV-1 promoter upon T cell stimulation, which facilitates proviral transcription. HIV-1 integrates into genomic regions marked by H3 citrullination and these proviruses are less prone to latency compared to those in non-citrullinated chromatin. Inhibiting PADI4 leads to compaction of the HIV-1 promoter chromatin and an increase of heterochromatin protein 1α (HP1α)-covered heterochromatin, in a mechanism partly dependent on the HUSH complex. Our data reveal a novel mechanism to explain HIV-1 latency and transcriptional regulation.
Upon infection with HIV-1 and proviral integration, the host enzyme PADI4 citrullinates histone H3 at the integration site, leading to non-repressed HIV-1 transcription. This explains how a few reservoir cells remain active despite antiviral therapy.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/31
/ 14/63
/ 38/15
/ 38/88
/ 38/90
/ 82/1
/ CD4-Positive T-Lymphocytes - metabolism
/ CD4-Positive T-Lymphocytes - virology
/ Citrullination - drug effects
/ Genomes
/ Histones
/ HIV
/ HIV Infections - drug therapy
/ Human immunodeficiency virus
/ Humanities and Social Sciences
/ Humans
/ Latency
/ Protein-Arginine Deiminase Type 4 - antagonists & inhibitors
/ Protein-Arginine Deiminase Type 4 - genetics
/ Protein-Arginine Deiminase Type 4 - metabolism
/ Proteins
/ Science
/ Transcription, Genetic - drug effects
/ Viremia
/ Virus Latency - drug effects
/ Viruses
