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Reactivation of latent HIV-1 by a wide variety of butyric acid-producing bacteria

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Abstract

Latently infected cells harbor human immunodeficiency virus type 1 (HIV-1) proviral DNA copies integrated in heterochromatin, allowing persistence of transcriptionally silent proviruses. It is widely accepted that hypoacetylation of histone proteins by histone deacetylases (HDACs) is involved in maintaining the HIV-1 latency by repressing viral transcription. HIV-1 replication can be induced from latently infected cells by environmental factors, such as inflammation and co-infection with other microbes. It is known that a bacterial metabolite butyric acid inhibits catalytic action of HDAC and induces transcription of silenced genes including HIV-1 provirus. There are a number of such bacteria in gut, vaginal, and oral cavities that produce butyric acid during their anaerobic glycolysis. Since these organs are known to be the major site of HIV-1 transmission and its replication, we explored a possibility that explosive viral replication in these organs could be ascribable to butyric acid produced from anaerobic resident bacteria. In this study, we demonstrate that the culture supernatant of various bacteria producing butyric acid could greatly reactivate the latently-infected HIV-1. These bacteria include Fusobacterium nucleatum (commonly present in oral cavity, and gut), Clostridium cochlearium, Eubacterium multiforme (gut), and Anaerococcus tetradius (vagina). We also clarified that butyric acid in these culture supernatants could induce histone acetylation and HIV-1 replication by inhibiting HDAC. Our observations indicate that butyric acid-producing bacteria could be involved in AIDS progression by reactivating the latent HIV provirus and, subsequently, by eliminating such bacterial infection may contribute to the prevention of the AIDS development and transmission.

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Abbreviations

AIDS:

Acquired immunodeficiency syndrome

ChIP:

Chromatin immunoprecipitation

HDAC:

Histone deacetylases

HIV-1:

Human immunodeficiency virus type 1

LTR:

Long terminal repeat

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Acknowledgments

We thank Dr. Marni Cueno for critical reading of the manuscript and expert language editing, and Mr. Hiroaki togami for technical assistance. 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, Dental Research Center, Nihon University School of Dentistry, Tokyo, the Takeda Science Foundation, the Waksman Foundation and “Strategic Research Base Development” Program for Private Universities from Ministry of Education, Culture, Sports, Science and Technology of Japan, 2010-2014 (S1001024).

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Authors and Affiliations

  1. 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

    Kenichi Imai & Takashi Okamoto

  2. Department of Microbiology, Division of Immunology and Pathobiology, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan

    Kenichi Imai, Kiyoshi Yamada, Muneaki Tamura & Kuniyasu Ochiai

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  1. Kenichi Imai
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Correspondence to Takashi Okamoto.

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Imai, K., Yamada, K., Tamura, M. et al. Reactivation of latent HIV-1 by a wide variety of butyric acid-producing bacteria. Cell. Mol. Life Sci. 69, 2583–2592 (2012). https://doi.org/10.1007/s00018-012-0936-2

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