The different SCFAs also induced expression of HIV-1 Tat protein in a dose-dependent manner. of variegation 3C9 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. (and (and as the molecule responsible for stimulating HIV-1 transactivation (Imai and Ochiai, 2011; Rhoifolin Imai et al., 2009; Imai et al., 2012a; Imai et al., 2012b; Imai et al., 2012c; Kantor et al., 2009). Butyric acid inhibits class-1/2 histone deacetylases (HDACs), leading to histone hyperacetylation and induction of viral gene expression Rhoifolin and replication. Different than the previous reports, we recently demonstrated that the different SCFAs from periodontal pathogens dose-dependently and additively promote lytic replication of Kaposis sarcoma-associated herpesvirus (KSHV) in acutely infected oral epithelial cells and latently infected B lymphocytes (Yu et al., 2014). Therefore, it would be interesting to test if the different SCFAs have comparable effects on HIV, which is a very different computer virus. Since cytokines and bacterial metabolic products released during inflammation are known to stimulate HIV transcription and productive replication, the infected oral cavity can become a site of enhanced viral replication (Bafica et al., 2004; Mbopi-Keou et al., 2002). In a chronic inflammation milieu such as gingivitis, CD4+ T-cells that are latently infected by HIV are likely present along with uninfected T-cells and macrophages (Fenouillet et al., 1989; Le Naour et al., 1992; Mabondzo et al., 1991; Neuveut et al., 1991; von Briesen et al., 1990). We therefore postulated that when latently infected CD4+ T-cells are exposed to Spp1 this environment of bacterial infection and chronic inflammation, the proviruses will become reactivated and this will lead to the release of infectious computer virus. In the present study, we investigated whether the different SCFAs can induce latent HIV-1 proviral transcription in T-cells. Several features of the metabolism of resting CD4+ T-cells work in an interdependent manner to ensure that latent proviruses remain transcriptionally inactive. First, quiescent T-cells contain minimal levels of P-TEFb, a cellular elongation factor that is an essential cofactor for the HIV transactivator protein Tat and purely required for efficient HIV transcription (Wei et al., 1998). In resting T-cells, CycT1 is usually expressed at minimal levels preventing P-TEFb assembly (Ghose et al., 2001). Second, epigenetic silencing due to recruitment of histone deacetylases (HDACs), histone methyltransferases (du Chene et al., 2007; Friedman et al., 2011; Keedy et al., 2009; Pearson et al., 2008) and DNA methylation (Blazkova et al., 2009; Kauder et al., 2009) greatly restrict transcription Rhoifolin initiation during latency. Finally, the transcription initiation factors NF-B and NFAT, which are used to reverse chromatin blocks on latent proviruses, are sequestered in the cytoplasm (Bosque and Planelles, 2008; Kinoshita et al., 1997; Nabel and Baltimore, 1987). Despite these multiple restrictions, stimulation of memory T-cells by cytokines or by T-cell receptor activation provides a powerful signal leading to the resumption of HIV transcription, replication and spread. We found that all SCFAs, except for acetic acid, are able to potently stimulate latent HIV-1 transcription in both Jurkat-T cells and main CD4+ T-cells in a dose-dependent and additive manner. Similar to our observations around the activation of KSHV in acutely infected oral epithelial cells and latently infected Rhoifolin B lymphocytes (Yu et al., 2014), we found that SCFAs potently inhibit the activity of class-1/2 HDACs in T-cells. In addition, SCFAs downregulate expression of the class-3 HDAC SIRT1 (sirtuin-1, silent information regulator-1), which is a NAD+-dependent HDAC (Guarente, 2000). SCFAs also downregulate expression of EZH2 (enhancer of Zeste homolog2) and SUV39H1 (suppressor of variegation 3C9 homolog1), two histone lysine methyltransferases (HLMTs) that suppresses gene expression through histone-3 (H3) di- and tri-methylation at Lys27 and Lys9, respectively (Cao et.