Short chain fatty acids potently induce latent HIV-1 in T-cells by activating P-TEFb and multiple histone modifications

Abstract

HIV patients with severe periodontitis have high levels of residual virus in their saliva and plasma despite effective therapy (HAART). Multiple short chain fatty acids (SCFAs) from periodontal pathogens reactivate HIV-1 in both Jurkat and primary T-cell models of latency. SCFAs not only activate positive transcription elongation factor b (P-TEFb), which is an essential cellular cofactor for Tat, but can also reverse chromatin blocks by inducing histone modifications. SCFAs simultaneously increase histone acetylation by inhibiting class-1/2 histone deacetylases (HDACs) and decrease repressive histone tri-methylation at the proviral LTR by downregulating expression of the class-3 HDAC sirtuin-1 (SIRT1), and the histone methyltransferases enhancer of Zeste homolog 2 (EZH2) and suppressor of variegation 3–9 homolog 1 (SUV39H1). Our findings provide a mechanistic link between periodontal disease and enhanced HIV-1 replication, and suggest that treatment of periodontal disease, or blocking the activities of SCFAs, will have a therapeutic benefit for HIV patients.