Reactivation of Latent HIV-1 Infection by the Periodontopathic Bacterium Porphyromonas gingivalis Involves Histone Modification

Abstract

Latently infected cells harbor the HIV-1 proviral DNA genome primarily integrated into heterochromatin, allowing the persistence of transcriptionally silent proviruses. Hypoacetylation of histone proteins by histone deacetylases (HDAC) is involved in the maintenance of HIV-1 latency by repressing viral transcription. In addition, periodontal diseases, caused by polymicrobial subgingival bacteria including Porphyromonas gingivalis, are among the most prevalent infections of mankind. Here we demonstrate the effects of P. gingivalis on HIV-1 replication. This activity could be ascribable to the bacterial culture supernatant but not to other bacterial components such as fimbriae or LPS. We found that this HIV-1-inducing activity was recovered in the lower molecular mass (<3 kDa) fraction of the culture supernatant. We also demonstrated that P. gingivalis produces high concentrations of butyric acid, acting as a potent inhibitor of HDACs and causing histone acetylation. Chromatin immunoprecipitation assays revealed that the corepressor complex containing HDAC1 and AP-4 was dissociated from the HIV-1 long terminal repeat promoter upon stimulation with bacterial culture supernatant concomitantly with the association of acetylated histone and RNA polymerase II. We thus found that P. gingivalis could induce HIV-1 reactivation via chromatin modification and that butyric acid, one of the bacterial metabolites, is responsible for this effect. These results suggest that periodontal diseases could act as a risk factor for HIV-1 reactivation in infected individuals and might contribute to the systemic dissemination of the virus.

Butyric acid retention in gingival tissue induces oxidative stress in jugular blood mitochondria

“…High BA levels have been correlated with diseases (Imai et al 2012;Imai et al 2009;Margolis et al 1988) and apoptosis induction (Kurita-Ochiai and Ochiai 2010), whereas, low BA levels have been correlated with colonic health (Maslowski et al 2009;Wong et al 2006). BA levels detected in this study were relatively low as compared to those that are related to diseases (Imai et al 2012(Imai et al , 2009Margolis et al 1988), however, we hypothesize that cells exposed to low BA levels but with prolonged exposure time could still affect cellular function, in particular, mitochondrial function.…”

“…BA levels detected in this study were relatively low as compared to those that are related to diseases (Imai et al 2012(Imai et al , 2009Margolis et al 1988), however, we hypothesize that cells exposed to low BA levels but with prolonged exposure time could still affect cellular function, in particular, mitochondrial function.…”

“…BA is an extracellular metabolite that helps the intestine maintain colonic health, serves as an energy source for colorectal cells, and positively influence immune responses (Hu et al 2011;Maslowski et al 2009;Wong et al 2006). However, high BA concentrations have been reported to be involved in reactivation of latent viral infection (Imai et al 2012(Imai et al , 2009) and induction of periodontal pathogenesis (Chen and Zychlinsky 1994;Kurita-Ochiai et al 2003;Kurita-Ochiai and Ochiai 2010).…”

Destructive effects of butyrate on the cell envelope of Helicobacter pylori

“…On the other hand, few studies have successfully cultured this bacterium from oral specimens. It has also been observed that the periodontaldisease-associated bacteria Porphyromonas, Prevotella and Fusobacterium can produce butyric acid (Kurita-Ochiai et al, 2006) and, recently, Imai et al (2009) indicated that butyric acid is the major short-chain fatty acid (SCFA) produced by P. gingivalis. Our previous study demonstrated that the cell supernatants of C. butyricum strain MIYAIRI 588 inhibited survival of H. pylori (Takahashi et al, 2000).…”

“…Indeed, some reports indicated that H. pylori is a transient member of the oral microflora, since the growth of H. pylori in the oral cavity is influenced by various factors such as temperature, pH, oxidation-reduction potential, the availability of nutrients, flow of saliva and antimicrobial substances ( Okuda et al, 2000Okuda et al, , 2003. Furthermore, Imai et al (2009) indicated that P. gingivalis culture supernatant contained butyric acid in high concentrations, from 6.7 to 14.7 mM. Moreover, Margolis et al (1988) indicated that the concentration of butyric acid in dental plaque was in the range of 14.4 to 20.0 mM.…”