Bacterial Short Chain Fatty Acids Push All The Buttons Needed To Reactivate Latent Viruses.

Abstract

The genomes of herpesviruses and HIV become silent during latency through multiple chromatin silencing mechanisms including: histone deacetylation, repressive histone methylation, and DNA methylation. Reactivation of the latent virus requires removal of the chromatin silencing marks and their replacement by activating modifications such as histone acetylation and activating histone methylation. In a complementary mechanism, RNA Polymerase II (RNAP II) elongation is regulated by the positive transcription elongation factor b (P-TEFb)-dependent phosphorylation of Ser2 residues on its C-terminal domain. In resting T-cells latently infected by HIV, expression of P-TEFb is restricted. We found that a group of short chain fatty acids (SCFAs) produced by oral bacteria not only promote histone acetylation but also change the histone methylation dynamics by decreasing repressive histone methylation while increasing activating histone methylation. SCFAs also block DNA methylation and activate P-TEFb to enable elongation of stalled RNA polymerase II. Thus these molecules do not simply act as histone deacetylase (HDAC) inhibitors as previously claimed. Instead, they impact multiple complementary epigenetic regulatory mechanisms to promote highly efficient reactivation of latent viruses.