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

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.

Epigenetic Metabolite Acetate Inhibits Class I/II Histone Deacetylases, Promotes Histone Acetylation, and Increases HIV-1 Integration in CD4+T Cells

“…In contrast to previous studies, which focused on the effect of butyrate on reactivation of HIV-1 in latently infected cells (6), the present results underscore the impact of acetate exposure on the permissiveness of primary human CD4 ϩ T cells to productive HIV-1 infection. Our observations revealed that acetate enhances the susceptibility of primary human CD4 ϩ T cells to productive HIV-1 infection (i.e., a greater proportion of HIV-1-infected cells) without affecting virus gene expression at the single-cell level ( Fig.…”

“…Resulting from the fermentation of indigestible food components by anaerobic commensal bacteria composing the gut microbiome (8-10, 14, 17, 19-24), SCFAs have been suggested to affect HIV-1-mediated disease progression (1)(2)(3)(4)(5)(6)(7)42). Previous studies have focused on the impact of the SCFA butyrate on reactivation of the provirus in cells latently infected with HIV-1.…”

Interaction between Endogenous Bacterial Flora and Latent HIV Infection

“…The progression to AIDS is influenced by host inflammatory responses and coinfection with other pathogens such as viruses, fungi, parasites, and bacteria (3,20,(42)(43)(44)(45). In particular, opportunistic infection frequently sets in when an HIV-infected individual is immunocompromised.…”

“…We found that among the various virulence factors produced by this Gram-negative anaerobe, a high concentration of butyric acid in the culture supernatant and the augmenting effect of HIV replication were abolished upon its removal. To confirm these observations, we attempted to comprehensively examine the human resident butyric acid-producing bacteria from various tissues (20). We found that bacterial culture supernatants of P. gingivalis, Fusobacterium nucleatum, Clostridium cochlearium, and Anaerococcus tetradius increased histone acetylation and efficiently induced HIV gene expression from the latent state.…”

“…We found that bacterial culture supernatants of P. gingivalis, Fusobacterium nucleatum, Clostridium cochlearium, and Anaerococcus tetradius increased histone acetylation and efficiently induced HIV gene expression from the latent state. Interestingly, these organisms (except P. gingivalis) produced the largest amounts of butyric acid in culture supernatants collected from among representative anaerobic organisms found in the oral, oral and gut, gut, and vaginal cavities, respectively (20). Furthermore, chromatin immunoprecipitation analysis revealed loss of HDAC1-AP-4 (transcriptional repressor complex of the HIV-1 provirus) occupancy at the long terminal repeat (LTR), whereas RNA polymerase II recruitment was increased.…”