title: 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.
authors.affiliation: Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Imai
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Ochiai
authors.forename: Takashi
authors.initials: T
authors.lastname: Okamoto
mesh_terms: D016866:Bacteroidaceae Infections / Q000276:immunology* / Q000378:metabolism; D020148:Butyric Acid / Q000378:metabolism; D002460:Cell Line; D002474:Cell-Free System / Q000378:metabolism / Q000382:microbiology / Q000821:virology; D002843:Chromatin / Q000378:metabolism; D018450:Disease Progression; D015658:HIV Infections / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D015497:HIV-1 / Q000276:immunology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D010518:Periodontitis / Q000378:metabolism / Q000382:microbiology* / Q000821:virology; D016966:Porphyromonas gingivalis / Q000276:immunology* / Q000378:metabolism; D011533:Proviruses / Q000276:immunology; D014775:Virus Activation / Q000276:immunology*; D017735:Virus Latency / Q000276:immunology*
chemical_list: D002843:Chromatin; D006657:Histones; D020148:Butyric Acid