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

Abstract

In this study, we investigated the effect of acetate, the most concentrated short-chain fatty acid (SCFA) in the gut and bloodstream, on the susceptibility of primary human CD4 ϩ T cells to HIV-1 infection. We report that HIV-1 replication is increased in CD3/CD28-costimulated CD4 ϩ T cells upon acetate treatment. This enhancing effect correlates with increased expression of the early activation marker CD69 and impaired class I/II histone deacetylase (HDAC) activity. In addition, acetate enhances acetylation of histones H3 and H4 and augments HIV-1 integration into the genome of CD4 ϩ T cells. Thus, we propose that upon antigen presentation, acetate influences class I/II HDAC activity that transforms condensed chromatin into a more relaxed structure. This event leads to a higher level of viral integration and enhanced HIV-1 production. In line with previous studies showing reactivation of latent HIV-1 by SCFAs, we provide evidence that acetate can also increase the susceptibility of primary human CD4 ϩ T cells to productive HIV-1 infection.IMPORTANCE Alterations in the fecal microbiota and intestinal epithelial damage involved in the gastrointestinal disorder associated with HIV-1 infection result in microbial translocation that leads to disease progression and virus-related comorbidities. Indeed, notably via production of short-chain fatty acids, bacteria migrating from the lumen to the intestinal mucosa could influence HIV-1 replication by epigenetic regulatory mechanisms, such as histone acetylation. We demonstrate that acetate enhances virus production in primary human CD4 ϩ T cells. Moreover, we report that acetate impairs class I/II histone deacetylase activity and increases integration of HIV-1 DNA into the host genome. Therefore, it can be postulated that bacterial metabolites such as acetate modulate HIV-1-mediated disease progression.

The colonic mucosa-associated microbiome in SIV infection: shift towards Bacteroidetes coincides with mucosal CD4+ T cell depletion and enterocyte damage

“…We found in our SIV-infected animals an association of acetate production with increasing contents of LPS in colonic tissue, which indicates that Gram-negative bacteria can have metabolic effects in SIV infection. According to a previous study, acetate enhances HIV integration into the genome of host cells by histone modifications 40 . Consequently, high colonic acetate concentrations at the time of mucosal peak viral load might enhance viral integration and Figure 6.…”

Intraperitoneal Injection of Acetate Protects Mice Against Lipopolysaccharide (LPS)‑Induced Acute Lung Injury Through Its Anti-Inflammatory and Anti-Oxidative Ability

“…Similarly, the interaction between acetate and HDAC6 has provided new therapeutic strategies for clostridium difficile infection [43]. In contrast, acetate increases the susceptibility of human CD4 + T cells to human immunodeficiency virus (HIV)-1 infection [44]. Further study is needed to determine if acetate exerts its protective effects by promoting histone acetylation.…”

Host mRNA decay proteins influence HIV-1 replication and viral gene expression in primary monocyte-derived macrophages

“…We then distinguished if the effects of UPF2 and SMG6 on HIV-1 replication were observed at a stage before the integration of the proviral DNA into the host genome or at a post-integration stage. Proviral DNA integration in control and UPF1-, UPF2- and SMG6-silenced MDMs was measured using a combined Alu-HIV-1 PCR as described in [49]. We observed no statistically significant differences between the amounts of integrated provirus across all conditions described (Fig.…”