Epigenetic Dysregulation of Translocating Bacteria from Progressive SIV Infection of Rhesus Macaques

Microbial translocation is a significant contributor to chronic inflammation in HIV-infected humans and has been associated with increased mortality and morbidity in individuals treated for long periods of time with antiretroviral medicines. Thus, there is interest in understanding the mechanisms underlying microbial translocation. Translocating bacterial taxa are not representative of the gut microbiota, with Proteobacteria appearing to preferentially translocate. To fully characterize translocating bacterial populations, we isolated bacteria from chronically SIV-infected rhesus macaque tissues collected at time of necropsy. IgG-seq of paired plasma and stool samples taken from the same animals did not show the presence of a systemic immune response to these bacterial species, suggesting that during progression to AIDS the immune system may be compromised to such a degree that the antibody response is impaired. Proteomic profiling of these bacteria identified a novel cytosine-specific methyltransferase as a potential driver of microbial translocation. In vitro growth assays of the translocating bacterial species with decitabine, a hypomethylating agent, showed significantly impaired growth for several species. RNA-seq of a subset of these species showed limited changes in transcripts when grown in the presence of decitabine as compared to controls, indicating that the drug may be bacteriostatic rather than bactericidal. Treatment of rhesus macaques with decitabine failed to significantly reduce the abundance of known translocator taxa in the gut microbiome and may have contributed to worsening intestinal damage.