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* Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and
Department of Microbiology, Nihon University School of Dentistry, Tokyo, Japan
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants-in-aid from the Ministry of Health, Labor and Welfare of Japan; the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Dental Research Center, Nihon University School of Dentistry, Tokyo; and the Japan Human Sciences Foundation.
2 Address correspondence and reprint requests to Dr. Takashi Okamoto, Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi 467-8601, Japan. E-mail address: tokamoto{at}med.nagoya-cu.ac.jp
3 Abbreviations used in this paper: LTR, long terminal repeat; Ac, acetylated; BHI, brain-heart infusion; ChIP, chromatin immunoprecipitation; csp, culture supernatant of Porphyromonas gingivalis FDC381; HAT, histone acetyltransferase; HDAC, histone deacetylase; SCFA, short-chain fatty acid; YY, Yin Yang.
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  B. Kantor, H. Ma, J. Webster-Cyriaque, P. E. Monahan, and T. Kafri Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infection PNAS, November 3, 2009; 106(44): 18786 - 18791. [Abstract] [Full Text] [PDF]
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