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.

Anaerobic Bacterial Fermentation Products Increase Tuberculosis Risk in Antiretroviral-Drug-Treated HIV Patients

“…The inverse correlation between lung oral anaerobes and pulmonary but not systemic CD4 + lymphocytes could be due to reduced lymphocyte recruitment to the lung or due to increased destruction at mucosal sites. SCFA produced by oral anaerobes activates latent HIV in lymphocytes (Imai et al, 2009) including primary human Th-17 cells (Das et al, 2015). Butyrate stimulated HIV replication of latent virus in the lung (Twigg Iii et al, 2008) could produce pulmonary CD4 + lymphocyte destruction.…”

Human adipose tissue as a reservoir for memory CD4+ T cells and HIV

“…Primary cellular reservoirs include memory CD4 T cells and macrophages; despite their low frequency (∼1 per million), latently infected CD4 T cells are the primary source of viral rebound in patients whose ART is interrupted [2]. Physiological induction of latent HIV in CD4 T cells occurs via activation of CD3/TCR, cytokines (IL2, IL7, IL15, IL6, and TNFα), TLR ligands, or free fatty acids [3]. Major tissue reservoirs include lymphoid tissue (lymph nodes, spleen, thymus, and bone marrow), gut-associated lymphoid tissue (GALT), and the central nervous system.…”

Epigenetic Metabolite Acetate Inhibits Class I/II Histone Deacetylases, Promotes Histone Acetylation, and Increases HIV-1 Integration in CD4+T Cells

“…Resulting from the fermentation of indigestible food components by anaerobic commensal bacteria composing the gut microbiome (8-10, 14, 17, 19-24), SCFAs have been suggested to affect HIV-1-mediated disease progression (1)(2)(3)(4)(5)(6)(7)42). Previous studies have focused on the impact of the SCFA butyrate on reactivation of the provirus in cells latently infected with HIV-1.…”

“…Considering that other SCFAs also act as inhibitors of class I/II HDAC activity (7,(35)(36)(37), their effect could be compounded by the action of acetate in a physiological setting. Therefore, further studies are required to provide a better understanding of the putative impact of bacterial metabolites such as SCFAs during HIV-1 pathogenesis.…”